Skip to main content

Ferroptosis, a new form of cell death: opportunities and challenges in cancer

Abstract

Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The fast-growing studies of ferroptosis in cancer have boosted a perspective for its usage in cancer therapeutics. Here, we review the current findings of ferroptosis regulation and especially focus on the function of ncRNAs in mediating the process of cell ferroptotic death and on how ferroptosis was in relation to other regulated cell deaths. Aberrant ferroptosis in diverse cancer types and tissues were summarized, and we elaborated recent data about the novel actors of some “conventional” drugs or natural compounds as ferroptosis inducers in cancer. Finally, we deliberate future orientation for ferroptosis in cancer cells and current unsettled issues, which may forward the speed of clinical use of ferroptosis induction in cancer treatment.

Background

Ferroptosis was first proposed by Dixon as a novel cell death in 2012 [1]. Unlike autophagy and apoptosis, ferroptosis is an iron-dependent and reactive oxygen species (ROS)-reliant cell death with characteristics mainly of cytological changes, including decreased or vanished mitochondria cristae, a ruptured outer mitochondrial membrane, and a condensed mitochondrial membrane [2,3,4,5,6]. These cell abnormalities resulted from the loss of selective permeability of plasma membrane due to intense membrane lipid peroxidation and the occurrence of oxidative stress (Table 1) [7].

Table 1 The main features of ferroptosis, apoptosis, autophagy, necroptosis, and pyroptosis

Researches indicated that ferroptosis could be triggered by diverse physiological conditions and pathological stresses in humans and animals [8]. Ferroptosis is gradually accepted as an adaptive feature to eliminate the malignant cells. It plays a pivotal role in the depression of tumorigenesis by removing the cells that are deficient in key nutrients in the environment or damaged by infection or ambient stress [9]. Studies have shown that the classic oxidative stress pathway was an important causative factor to induce ferroptosis. Although cancer cells are under continuous oxidative stress with an exquisite balance between thiols and catalytic iron, ferroptosis does not often happen in the cancer development [10]. The underlying molecular mechanisms remain poorly understood. We herein review the occurrence and regulation of ferroptosis in various cancer cells. The opportunity and challenge of cancer treatment based on ferroptosis will be detailed, which was desired to prosper new strategies for cancer therapy of clinical value.

Ferroptosis, from a cancer perspective: an overview

Ferroptosis was first observed in oncogenic Ras-expressing human foreskin fibroblast cell line by a battery of small compounds considered as ferroptosis-inducing agents (FIN), including erastin and Ras-selective lethal small molecule 3 (RSL 3). With the following studies, the relationship of Ras oncoprotein with ferroptosis becomes agnostic. Some Ras WT cells including fibrosarcoma cells, kidney tubule cells, and T cells are vulnerable to erastin, but the RMS13 rhabdomyosarcoma cells with Ras mutation were resistant to erastin and RLS3. Indeed, the ferroptosis inducer artesunate/erastin can promote ferroptosis in a Ras-reliant way in pancreatic cancer or transformed fibroblastic cells, while in a Ras-independent manner in leukemia cells [6, 11].

Emerging evidence implicated that ferroptosis may be an adaptive process which was critical for eradicating the carcinogenic cells [1]. More clues for this role of ferroptosis can be derived from recent researches of the tumor suppressor P53 (TP53). The acetylation-defective mutant TP533KR lost the ability to induce cell senescence, apoptosis, and cell-cycle arrest, which were the main functions of TP53 in tumor suppression. Impressively, TP533KR can still hold the capacity of inhibiting tumorigenesis due to its ferroptosis induction [12,13,14]. An argument does emerge that P53 expression may promote, limit, or detain the outset of ferroptosis in certain cells or conditions (Fig. 1). These opposite jobs of p53 in operating the process of ferroptotic cell death were executed by different mechanisms, including effects on metabolic genes transcription, post-translational regulation or by virtue of P53-P21 axis [15, 16]. The bidirectional regulation of ferroptosis by P53 in a cell-specific or context-dependent manner needs to be further investigated. Moreover, it is still obscure that what kind of role P53-target genes take part in manipulating of the ferroptotic cell death [17]?

Fig. 1
figure 1

P53 regulate ferroptosis. P533KR cannot elicit apoptosis activity, it retains the ability to promote ferroptosis. GLS2 and SAT1 contribute, at least in part, to P533KR-mediated ferroptosis. P533KR completely retains the ability to regulate the expression of SLC7A11. Interestingly, WTP53 inhibits ferroptosis via blocking the DPP4 activity. And WTP53 can delay ferroptosis by promoting the expression of P53 transcriptional target CDKN1A. However, P533KR is unable to induce P21. Other P53 mutants, P534KR, P53P47S, and TP53KO, cannot induce ferroptosis and weaken the blocking of cell growth

Ferroptosis is programmed necrosis mainly triggered by extra-mitochondrial lipid peroxidation arising from an iron-dependent ROS accretion. Excessive iron originally from aberrant iron metabolism or maladjustment of two major redox systems (lipid peroxidation and thiols) was the main incentive factors of ROS production. Glutathione (GSH), a thiol-containing tripeptide, synthesis is determined by the constant import of cysteine (Cys2) by the cell surface Cys2/glutamate antiporter xCT (Fig. 2).

Fig. 2
figure 2

Mechanism of ferroptotic cell death. System xc- transports intracellular Glu to the extracellular space and extracellular Cys2 into the cell, which is then transformed into Cys for GSH synthesis. GPX4 reduces the endogenous neutralization of PUFAs-OOH to PUFAs-OH, ultimately reducing ROS accumulation. Excess irons are the basis for ferroptosis execution. Circulated iron was combined with transferrin in the form of Fe3+, and then it entered into cells by TFR1. Iron in Fe3+ form was deoxidized to iron in Fe2+ by iron oxide reductase STEAP3. Ultimately, Fe2+ was released into a labile iron pool in the cytoplasm from the endosome mediated by DMT1

The activation of Ras-mitogen-activated protein kinase (MEK) signaling can attribute to the sensitivity of cancer cells to ferroptosis, resulting from its promoting iron abundance in cancer by governing the expression levels of the transferrin receptor and ferritin [2, 7, 8]. And the overactive Ras-MEK pathway may enhance ROS generation via inhibiting cystine (Cys2) uptake or mitochondrial voltage-dependent anion channel 2/3 (VDAC 2/3) and consequently sensitize cancer cells to ferroptosis [18, 19]. But scientist and skeptics argued that the conclusion is unreliable because the MEK inhibitor U0126 was used in these above studies. Compared with U0126, the special MEK1/2 inhibitor, PD0325901 cannot halt cell ferroptotic cell death induced by FIN. So MEK activity is not indispensable for ferroptosis [20, 21]. Other signal pathways were also pinpointed to regulate the process of cell ferroptotic death, e.g., Keleh-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2), lymphoid-specific helicase (LSH), Egl nine homolog 1 (EGLN1)/cellular myelocytomatosis oncogene (c-Myc), mevalonate (MVA), sulfur-transfer, mucin 1 C-terminal (MUC1-C)/system xc- (xCT) and heat shock factor-1 (HSF1)-heat shock protein beta-1 (HSPB1) pathway [5]. RNAi against Fms-like tyrosine kinase 3 (Flt3) saves cells from ferroptosis by limiting lipid peroxidation and inactivating p22phox which back the role for Flt3 kinase in ferroptosis. A new study indicates that adenosine 5′-monophosphate-activated protein kinase (AMPK)-mediated the phosphorylation of Beclin1 (BECN1) directly blocks the activity of system xc- and thus results in the occurrence of ferroptosis [22, 23]. Recent investigations have unraveled a perplexing network in the ferroptosis regulation which was shown in Fig. 3.

Fig. 3
figure 3

The regulatory network of ferroptosis. PHKG2, IREB2, and CISD1 play an important role in ferroptosis by their function in iron metabolism balance. The phosphorylation of HSP27 induces ferroptosis resistance through blocking cytoskeleton-mediated iron absorption. EGLN1 can upregulate LSH expression by limiting HIF 1α. LSH inhibits ferroptosis by affecting metabolism-associated genes including SCD1, GLUT1, and FADS2. Also, protein kinase C-mediated HSPB1 is a negative regulator of ferroptosis by inhibiting ROS production and reducing iron uptake. The p62-Keap1-Nrf2 pathway plays a vital role against ferroptosis by regulating Nrf2-targeted genes HO-1, FTH1, and NQO1. AMPK-mediated BECN1 phosphorylation and BAP1 directly represses system xc- activity, leading to the elevated ROS level and ferroptosis. MUC1-C binding with CD44v promotes the stability of system xc-. The inhibition of CDO1 restores the levels of GSH and increases ROS. Methionine can be converted to S-adenosylhomocysteine and Cys through the sulfur transfer pathway, which is essential for GPX4 biosynthesis. IPP and CoQ10 are the important products of the MVA pathway, which promotes GPX4 synthesis. FIN56 treatment also reduces CoQ10 by modulating SQS. VDAC2/3 and CARS are positive regulators of ferroptosis. ROS accumulation requires the activation of PUFAs by ACSL4 and LPCAT3. And LOX directly catalyzes the peroxidation of phospholipid PUFAs

Interestingly, microRNA and long non-coding RNA (lncRNA) are increasingly recognized as the crucial mediators in the regulation of ferroptosis (Table 2). The cytosolic lncRNA P53RRA can promote ferroptosis via nuclear sequestration of P53. P53RRA interplays with the RNA recognition motif (RRM) domain of Ras GTPase-activating protein-binding protein 1 (G3BP1), resulting in the combination of G3BP1 with P53, which cause more P53 custody in the nucleus and less sequestration of p53 in the cytoplasm [24]. P53RRA increased the intracellular concentrations of iron and lipid ROS by means of the augmented P53 pathway. Taken together, the cytosolic P53RRA-G3BP1 is a novel mechanism for inducing ferroptosis in lung adenocarcinoma.

Table 2 Non-coding RNA associated with ferroptosis

In melanoma cell lines G-361 and A375, miR-9 can inhibit ferroptosis via targeting glutamic-oxaloacetic transaminase 1 (GOT1), an enzyme via glutaminolysis converting glutamine (Gln) ultimately to α-ketoglutarate (α-KG), which can promote ROS accumulation and thus irritate ferroptosis [25]. Knockdown miR-9 elevated the level of GOT1 and a-KG, which subsequently increased the sensitivity of cells to erastin- and RSL3-induced ferroptosis. Intriguingly, the other study showed that miR-137 impedes ferroptosis through directly suppressing solute carrier family 1 member 5 (SLC1A5), which is a major receptor for Gln uptake [26]. Knockdown of miR-137 can enhance the antitumor activity of erastin by enhancing ferroptosis.

As a specific light-chain submission of the Cys2/glutamate (Glu) antiporter, solute carrier family 7 member 11 (SLC7A11) plays a critical role in the negative regulation of ferroptosis. Researches showed that miR-375, miR-27a, miR-26b, and As-SLC7A11 (antisense lncRNAs) could suppress the transcription of SLC7A11 mRNA and impair the strength of its protein [27,28,29,30]. So, it is plausible that these miRNAs can promote ferroptosis by targeting SLC7A11.

The Nrf2 is the vital inhibitor of ferroptosis due to its ability to inhibit cellular iron uptake, limiting ROS production, and upregulating SLC7A11. First, miR-7 and miR-200a readily induce the activation of the Nrf2 pathway by repressing Keap1 expression [31, 32]. Contrastingly, miR-28 suppresses Nrf2 expression in a Keap1-independent way [33]. Second, both miR-101 and miR-455 can promote Nrf2 nuclear accumulation by targeting Cullin-3 (Cul3) [34, 35]. Finally, miR-153, miR-142-5p, miR-27a [36], miR-144 [37], miR-93 [38], miR-34a [39], miR-365-1, miR-193b, and miR-29-b1 [40] can decrease Nrf2 level through different mechanisms. These results indicated that miRNA might modify ferroptosis by means of regulating the expression of Nrf2.

It was confirmed that iron overload could contribute to ferroptosis in cancer. The iron metabolism-related genes, such as transferrin (TF), transferrin receptor 1 (TFR1), ferroportin (FPN), divalent metal transporter 1 (DMT1), ferritin heavy chain 1 (FTH1), and ferritin light chain (FTL), were the critical mediators in the ferroptosis procedure. Based on the existing research findings, miRNAs were also involved in the regulation of iron export, storage, utilization, and uptake. MiR-20a and miR-485-3p can reduce iron output by targeting FPN genes [41, 42]. MiR-210 and miR-152 inhibit the expression level of TFR, thereby reducing the uptake of TF [43, 44]. Concurrently, the expressions of miR-200b and miR-Let-7d effectively reduce iron accumulation by inhibiting the expression of FTH and DMT1-iron-responsive element (IRE), respectively [45, 46].

Beyond that, previous studies have confirmed that ROS generation requires the activation of polyunsaturated fatty acids (PUFAs) by Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3). MiR-3595 [47], miR-205 [48], miR-224-5P [49], miR-19b-3p, miR-130a-3p, miR-150-5p, miR-144-3p, miR-16-5p, miR-7a-5p, and miR-17-5p [50] can decrease the expression of ACSL4. It is conceivable but not yet demonstrated that these miRNAs can regulate ferroptosis by targeting ACSL4.

Ultimately, ROS is the indispensable molecule in the process of ferroptosis. Previous studies have confirmed that miRNAs are closely related to redox signaling and ROS production, and we can further speculate that miRNAs can regulate ferroptosis by regulating the expression of ROS. MiR-206 significantly induces ROS accumulation by binding to the mRNA of superoxide dismutase 1 (SOD1) [51]. MiR-155 increases the generation of ROS by inducing Foxo3a deficiency [52]. Also, miR-25 and miR-448-3p have been proved to reduce ROS level by targeting the nicotinamide adenine dinucleotide phosphate-oxidase (NOX) [53, 54].

Ferroptosis, as an expanding network of programmed cell death in cancer

Apart from apoptosis and autophagy, other programmed cell death such as programmed necrosis was discovered. Ferroptosis, as well as necroptosis, parthanatos, and pyroptosis, are all belonging to the programmed necrosis, which was carried out by a specific program of genetically encoded cellular machinery demolishing the cell in an ordered fashion [9]. Over the latest 5 years, an astonishing boost in our perception of ferroptosis has been seen, and it was linked with apoptosis, autophagy, and other programmed necrosis which are tentatively investigated.

Ferroptosis and apoptosis: switch, synergism, or antagonism?

Recently, a growing research suggested the interconnection of ferroptosis and apoptosis. Besides preventing tumorigenesis by cell-cycle arrest and cell apoptosis induction, the canonical tumor suppressor protein P53 can also induce ferroptosis in certain conditions. Zheng et al. designed a novel type of P53 complex named metal organic network-P53 (MON-P53), which is tannic acid integrated with ferric ions forming MON on the external of the P53 plasmid [55]. When MON-P53 was internalized, ferric ions can induce Fenton reaction which will cause ROS generation. In vivo and vitro experiment, the dominant ferroptotic cell death, apart from cell apoptosis, was observed in the MON-P53-treated cells. The tumor growth was suppressed, and the life span of tumor-bearing mice was also prolonged. Therefore, this approach will direct a ferroptosis/apoptosis hybrid anti-cancer therapy [9].

Conversely, ferroptotic agents such as artesunate and erastin can induce the unfolded protein response (UPR) which sequentially promotes the expression of P53 upregulated modulator of apoptosis (PUMA) via C/EBP-homologous protein (CHOP) in the P53-independent way [56]. PUMA can enhance the function of apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting cell apoptosis (Fig. 4). This observation of ferroptotic agent-mediated sensitization to TRAIL-induced apoptosis implies ferroptosis inducer combined with TRAIL can strongly augment the tumoricidal efficacy. Another opinion is that metabolic or other alterations related to the irritation of ferroptosis biochemically block apoptosis occurrence. Cells that were subjected to ferroptosis due to cysteine (Cys) deprivation have about 10% of the normal level of intracellular glutathione (GSH). The power of reduced GSH may be necessary for the cascade activation of caspases-3 and-8. Therefore, cells’ lack of GSH cannot activate caspases correctly [10, 57].

Fig. 4
figure 4

Cross-talk between ferroptosis, apoptotic, and autophagy in cancer. Autophagy can modulate cell sensitivity to ferroptosis through various pathways. Erastin, artesunate, MON-P53, and Cys closely link ferroptosis with apoptosis. ELAVL1 promoted autophagy by binding to the AU-rich elements within the F3 of the 3′-untranslated regions of BECN1 mRNA. BECN1 can promote ferroptosis via directly blocking system xc-

Autophagy degrades ferritin to facilitate ferroptosis

Autophagy is a lysosome-dependent degradation pathway. The study provided data that the activation of autophagy pathway can degrade ferritin and then trigger ferroptosis in cancer cells [58]. Ferritinophagy, the autophagic turnover of ferritin, is critical to induce ferroptosis [59]. Further study indicated that BECN1 generation from the stimulation of upregulated embryonic lethal, abnormal vision, Drosophila-like 1 (ELAVL1) was responsible for the activation of autophagy in erastin- or sorafenib-irritated ferroptosis [60].

Autophagy can contribute to ferroptosis via the generation of lysosomal ROS and providing available labile iron via NCOA4-mediated ferritinophagy. And pharmacological blockage of autophagy weakens drug-induced ferroptosis in cancer cells. Genetic knockout of autophagy-related 5 (Atg5) and Atg7 limited erastin-induced ferroptosis by decreasing lipid peroxidation and intracellular ferrous iron levels. Significantly, blockage of nuclear receptor coactivator 4 (NCOA4), which was a choosy cargo receptor for ferritinophgay, suppresses ferritin degradation and inhibits ferroptosis. Contrarily, NCOA4 overexpression reinforces ferritin degradation and then drives ferroptosis. Autophagy supplies available labile iron via NCOA4-mediated ferritinophagy to the process of ferroptosis [61,62,63]. These results unraveled the molecular interactions between ferroptosis and apoptosis, and ferroptosis is an autophagic cell death process [64]. But in the absence of ferroptosis, prolonged iron mediates ROS accumulation and triggers autophagy and then results in autosis. Ferroptosis and autophagy can motivate cell death occurrence separately in breast cancer cells with siramesine and lapatinib treatment [58]. But contrastly, Buccarelli et al. reported that the blockage of autophagy using quinacrine can enhance glioblastoma stem cells (GSC) sensitivity to temozolomide by means of ferroptotic cell death [65].

Recent research shows that SOCS1 is required for p53 activation and the regulation of cellular senescence. SOCS1 can regulate the expression of p53 target genes such as reducing the expression of the cystine transporter SLC7A11 and the levels of glutathione, and it therefore sensitize cells to ferroptosis [66].

Although the mechanism among diverse types of regulated cell death has distinctive morphological and biochemical traits, some crosstalk still prevails between regulators and components of these various processes [67, 68]. The pathway of ferroptosis was linked with that of oxytosis by transactivating BH3-interacting domain death agonist (BID), the pro-apoptotic member of Bcl-2 family proteins, which converged to mitochondrial damage [69]. MiR137 was identified as a central mediator among apoptosis, autophagy, and ferroptosis [26]. HSPB1 is a small heat-shock protein that is crucial in controlling autophagy and ferroptosis [70]. Erastin can simultaneously induce the ferroptosis and necroptosis in HL-60 cell line [6]. Therefore, explicating how these pathways of regulated cell death are interplayed at the molecular level and how these pathways could be mapped and integrated will advance new ways to systematical research on this field. Discerning the critical factors such as ncRNAs should enable these processes to be therapeutically targeted and would be highly desired.

Aberrant ferroptosis in diverse cancer types and tissues

The susceptibility of different types of cancer cells to ferroptosis was significantly different. NCI-60, a panel of different cancer cell lines from eight various tissue types, recommended by the US National Cancer Institute Developmental Therapeutics Program. Among them, diffuse large B cell lymphomas and Renal cell carcinoma are more susceptible to erastin-induced ferroptosis than other cancer cells from the six tissues (the breast, lung, colon, melanocytes, central nervous system, and ovary) [6]. Some argue that the sensitivity of different cell lines to ferroptosis is different because of the difference of their basic metabolic state. Numerous studies have confirmed the pivotal role of ferroptosis in killing cancer cells and suppressing cancer growth. Further investigations showed that chemotherapeutic drugs such as cytarabine/ara-C, cisplatin, doxorubicin/Adriamycin, and temozolomide combining with the ferroptosis inducer erastin gained a remarkable synergistic effect on their anti-tumor activity [3]. The prognosis is better than traditional chemotherapy alone. Here, we summarize the possible mechanism of ferroptosis in various cancer types and putative indictor of ferroptosis for clinical application.

Hepatocellular carcinoma

Ferroptosis was one of the underlying mechanisms in sorafenib treating HCC. HCC cells with the retinoblastoma (RB) protein deficiency had 2–3 times higher death rate more than that of cells with a normal level of RB protein [71]. This susceptibility of HCC with deactivated RB protein to ferroptosis was due to the augment of oxidative stress response in cells from increased reactive oxygen concentration in mitochondria. Metallothionein-1g (MT-1G) is a novel negative regulator of ferroptosis in HCC. MT-1G knockdown contributed to sorafenib-induced ferroptosis by increasing lipid peroxidation and GSH depletion. CDGSH iron sulfur domain 1 (CISD1) and ACSL4 inhibition promote erastin-induced ferroptosis in HCC. Low-density lipoprotein (LDL)–docosahexaenoic acid (DHA) nanoparticles cause cell death in HCC cells through the ferroptosis pathway. The p62-Keap1-Nrf2 pathway plays a vital role in saving HCC cells from ferroptosis, and Ras/Raf/MEK pathway is reported to be a critically important target for ferroptosis in treating HCC [72].

Colorectal cancer

Xie et al. reported that colorectal cancer was resistant to ferroptosis resulting from the inhibition of dipeptidyl-peptidase-4 (DDP4) activity by TP53 in a transcription-independent way [12]. P53 loss promotes DDP4 gathering to plasma-membrane and thus augments DDP4-dependent lipid peroxidation, eventually causing ferroptotic cell death.

Gastric cancer

Hao et al. found that erastin irritates ferroptosis in GC cells [73]. Ferrostatin-1 and liproxstatin-1 can reverse this effect. C-Myc increases the expression of cysteine dioxygenase type 1 (CDO1), facilitating ferroptosis occurrence. Mechanistically, CDO1 suppression leads to the resistance of GC cells to erastin-induced ferroptosis by restoring cellular glutathione peroxidase 4 (GPX4) expression and GSH levels, and also by decreasing ROS generation. Another study reported that the CD44 variant (CD44v) stabilizes xCT at the plasma membrane and increases Cys2 uptake for GSH synthesis, blocking the ROS-induced stress signaling, and thus confer to ferroptosis resistance in GC cell [74, 75].

Ovarian cancer

Ovarian cancer cells are characteristics of ferroptosis susceptibility because of excess iron overload by its tumor-initiating cells (TICs), which have overexpressed TFR1 and decreased iron efflux pump FPN level [76]. Artesunate (ART) can induce ferroptosis in a ROS-dependent way in ovarian cancer. Ferrostatin-1 can significantly reverse ART-induced cell ferroptosis, but transferrin pretreatment augments the ferroptosis of ovarian cancer cells induced by ART via enhancing cellular iron level [77].

Prostate adenocarcinoma

Erastin induces ferroptosis in Ras-carrying human prostate adenocarcinoma cells. The phosphorylation of HSF1-dependent HSPB1 contributes to the ferroptosis resistance to erastin through inhibiting lipid ROS accumulation and iron uptake [70]. HSPB1 inhibition specifically increased erastin-induced ferroptosis by facilitating iron accumulation from the upregulation of TFR1 and slight reduction of FTH1 expression.

Breast cancer

Ma et al. reported that siramesine and lapatinib induce ferroptosis by increasing iron-dependent ROS productions, and CDO1 overexpression can exacerbate ferroptotic cell death by the further accumulation of high-level ROS result from the decreased GSH levels in breast cancer cells [58]. In contrast, MUC1-C can upregulate the GSH expression by its formation of a complex with CD44v, which cause the cripple of ferroptosis in breast cancer cells [74].

Lung cancer

Ferroptosis of lung cancer cell was first induced by erastin in the K-ras mutated A549 cells [2]. And the following report shows that erastin sensitizes lung cancer cells to cisplatin in ferroptosis manner by GSH reduction and GPXs inactivation [19]. Cysteine desulfurase (NFS1), as an iron-sulfur cluster biosynthetic enzyme, can protect cells from ferroptosis under the high-oxygen tension by sustaining the iron-sulfur cofactors. Coinhibition of NFS1 and Cys transport can evoke ferroptosis in vitro and suppress tumor growth [20].

Rhabdomyosarcoma

High level of GSH biosynthesis is essential for RMS cells to grow and become multidrug resistant. GPX4 inhibition using RSL3 and erastin can induce ferroptosis in RMS13 cells by lessening GSH level [21]. Another possible reason for high susceptibility of RMS13 cell lines to erastin and RSL3 was related to its higher activity of intrinsic Ras/extracellular signal-regulated kinase (ERK). But contrastingly, the RMS13 cells with oncogenic Ras mutation were resistant to the oxidative stress-induced ferroptosis.

Hematological malignancies

Diffuse large B-cell lymphoma (DLBCL) cells were notably one of the most sensitive to ferroptosis inducer in the eight cell lines harvested from various tissues [78]. It is proved that the enhanced sensitivity might be due to its weakness in the sulfur transfer pathways, which causes more extracellular Cys and Cys2 required for cells survival [79]. Yu et al. reported low-dose erastin could remarkably increase the ability of cytarabine and doxorubicin to kill non-APL acute myeloid leukemia (AML) cells by irritating both necroptosis and ferroptosis [80].

Ferroptosis-induction cancer therapy

Since erastin, a novel compound is found in human tumor cells in 2003 [81]. It was first identified as a ferroptosis inducer in 2012 [8], several clinical drugs have also been found to hold a capacity of inducing ferroptosis in cancer cells.

Chemotherapeutic agents

Sulfasalazine

SSZ is recently recognized as a system xc- inhibitor [41]. xCT expression has circadian rhythm and the expression of TFR1 was affected by the circadian organization of molecular clock. Bmal1 and the clock regulate the circadian rhythm of xCT expression. The clock-controlled gene c-Myc rhythmically activated the transcription of the TfR1 gene. SSZ has been reported to disrupt the circadian rhythm of transferrin receptor 1 gene expression and thus it was plausible that SSZ may affect iron metabolism [82,83,84]. Toyokuni et al. report that sulfasalazine inhibits Cys2 uptake via system xc-, resulting in ferroptosis in glioma cells [85]. Based on the circadian rhythm of xCT, SSZ has different effects on inducing ferroptosis at various times. But some argued that ferroptosis was not observed in the mouse embryonic fibroblasts treated with sulfasalazine [86]. One reasonable interpretation was the discrepancy of different cell lines on the sensitivity to ferroptosis.

Artesunate

ART and its derivatives can produce ROS and cause oxidative stress in cancer cells. In pancreatic ductal adenocarcinoma, head and neck cancers (HNCs), and ovarian cancer cells, the mechanism underlying the antitumor effect of ART was ferroptosis-induction [87]. However, because of the activation of Nrf2-antioxidant response element signaling pathway, the ferroptosis induction of artesunate can be partially attenuated in some cisplatin-resistant HNCs [88]. So Nrf2 inhibition via silencing Keap1 helps the reversal of ferroptosis resistance to artesunate in HNC cells.

Temozolomide

TMZ markedly induces system xc- expression via the activation of activating transcription factor 4 (ATF4) and Nrf2 pathway in glioblastoma multiforme (GBM) cells [89]. Cystathionine γ-lyase (CTH), an enzyme in the transsulfuration pathway, is induced after temozolomide treatment, which can supply Cys when system xc- is blocked. Based on the finding of erastin facilitating ferroptotic cell death to temozolomide, thus, the combination of TMZ and erastin maybe a promising therapy in GMB treatment [90].

Cisplatin

From the screening among five chemotherapeutic drugs, cisplatin was found as a ferroptosis-inducer. Cisplatin exerts its cytotoxic effects on A549 and HCT116 cells to undergo ferroptosis by reduced GSH depletion together with GPXs inactivation [19].

Targeted agents

Sorafenib

Sorafenib was first identified as a ferroptosis-inducer in HCC cell lines [91]. System xc- inhibition and GSH depletion, the accomplices for ROS accumulation, were the main mechanism for sorafenib-induced ferroptosis. Haloperidol, as a sigma receptor 1 antagonist, can bolster erastin and sorafenib-induced ferroptosis by stimulating cellular iron accumulation, GSH depletion, and lipid peroxidation [92]. But the overactive p62-keap1-Nrf2 pathway will weaken the ferroptosis process, owing to the target genes of Nrf2 including heme oxygenase-1 (HO-1), FTH1, and quinone oxidoreductase-1 (NQO1) which can directly inhibit ROS accretion. Nrf2 inhibition using genetic tools or drugs could remarkably reinforce the anti-tumor effect of sorafenib [93].

Lapatinib and BAY87–2243

Lapatinib is a tyrosine kinase inhibitor. It can incite ferroptosis in breast cancer cells when it was used together with siramesine [58]. BAY87-2243, a robust inhibitor of NADH-coenzyme Q oxidoreductase, can promote ferroptosis in a dose-dependent manner on a series of BRaf (V600E) melanoma cell lines [94].

Others

Lanperisone

Lanperisone promotes ROS production to kill K-Ras-mutant mouse embryonic fibroblasts in ferroptotic ways. And it also induces lung cancer cell ferroptotic death by inhibiting Cys2 uptake in the mouse model [95].

Besides the clinically approved drugs, two antibiotics such as salinomycin and ironomycin can promote ferroptosis in colon cancer cells via interfering with iron metabolism allowing for ROS production [65]. Other natural compounds such as bromelain [50], baicalein, artenimol, artemisinin, cotylenin A (CN-A) [11], and various vitamins can regulate cell ferroptotic death by acting on the lipid peroxidation and ROS occurrence (Table 3). Numerous nanomaterials have also been prospered for ferroptosis-based cancer therapy. Most of them are iron-based nanomaterials, which can be used as carriers of certain genes, such as P53 and ACSL4, to inhibit or promote the expression of certain critical molecules correlated with ferroptosis [55, 94, 96].

Table 3 Drugs and compounds associated with ferroptosis

Challenges

How does ferroptosis interact with other cell death at the molecular level and how could these pathways be mapped and integrated into the cellular events?

How does ncRNA regulate the process of ferroptotic cell death?

Can ferroptosis enhance the cell immunogenicity to the host and thereby evoke an adaptive immune response, as shown in necroptotic cell death?

Are the ferroptosis inducers effective in killing the cancer cells in pre-clinical or clinical trials?

Conclusion & perspective

Collectively, ferroptosis has taken a full expectation from us to provide a new approach in anti-tumor therapies. Current researches have mainly focused on the eradication of residual or resistant cancer cells, where ferroptotic cell death emerges to be a new cell death for this purpose (Fig. 5). Conspicuously, obtaining a mesenchymal cell state (e.g., epithelial-mesenchymal transition (EMT) or cancer stem cells) has been suggested to determine metastatic dissemination and chemo-resistance [97]. More recently, the cancer cells with the high-mesenchymal state have arisen as a vital mechanism of both acquired and de novo resistance to targeted therapies [98, 99]. This therapy-resistant mesenchymal cancer cells have bred a state of non-oncogene addition to GPX4, which inhibition will intuitively result in ferroptosis. Consistently, persistent cancer cells which are nominated to escape from conventional cytotoxic treatment via a dormant state tumor showed an identically selective dependency on the GPX4 pathway [100, 101]. Therefore, ferroptosis might be considered a viable therapeutic strategy to reverse therapy-resistance in cancer strategy.

Fig. 5
figure 5

Perspectives of ferroptosis in cancer therapeutics. Ferroptosis can be as a novel cell death for killing mesenchymal-state cells or as an important synergist for immunotherapy and chemotherapy. P53 regulate ferroptosis sensitivity in a cell-type-special way. A large number of small molecules and drugs regulate ferroptosis in a Ras-dependent or -independent manner

Ferroptosis is a kind of programmed necrosis, which is accepted to be more immunogenic than apoptosis. Due to damage associated with molecular patterns (DAMPs) (e.g., HMGB1) release, ferroptosis was considered as a pro-inflammatory process [102]. By deliverying chemoattractant signals, ferroptosis hold the ability to recruit and activate immune cells at tumor sites, which provide the possibility of ferroptosis inducer as a suitable enhancer for anti-tumor immunotherapy treatment such as checkpoint-inhibitor [103]. Indeed, a large number of immune cells were observed inside the tumor mass when the mouse tumor xenografts underwent cell ferroptotic death induced by ultrasmall nanoparticles [104]. However, scientist skeptics argued that ferroptosis and necroinflammation did not have an unequivocal relationship [102].

Several studies of drug re-position suggest that “conventional” agents (i.e., SASP and artesunate) have antitumor therapeutic effects by activating ferroptosis [105]. As a chemo-sensitizer by ferroptosis-induction, erastin can be used with various drugs such as cisplatin, temozolomide, doxorubicin/adriamycin, and cytarabine/ara-C in different type cancers. Albeit there is limited knowledge of the elaborated mechanism in the ferroptosis pathway that is engaged by current ferroptosis inducers, ferroptosis may provide a new form of cell death for approaching the reversal of drug-resistance and boosting the host immune system. Although it was promising from the advantages of ferroptosis in cancer therapeutics, ferroptosis is still waiting for formal addressing in a pre-clinical setting and clinical achievability, partially due to the complexity of it observed in different contexts such as P53 or Ras-mutant cancer cells. Another challenge is that ferroptosis induction such as GPX4 inhibitor affects the development and function of nervous system and kidney, by causing GPX4 gene which is fundamental for embryonic development and some adult tissue homeostasis in mice [106]. In addition, another noticeable issue is that the occurrence of ferroptotic resistance, which was originally observed in the Hela cells with the erastin treatment. The resistance mechanism was the HSP27 overactivation by suppressing cytoskeleton-mediated iron absorption [107].

Abbreviations

ACSL4:

Acyl-CoA synthetase long-chain family member 4

AML:

Acute myeloid leukemia

AMPK:

Adenosine 5-monophosphate-activated protein kinase

ART:

Artesunate

As-SLC7A11:

Antisense lncRNAs

ATF4:

Activating transcription factor 4

Atg5:

Autophagy-related 5

BAP1:

Breast cancer susceptibility gene 1-associated protein 1

BECN1:

Beclin1

BID:

BH3 interacting domain death agonist

CARS :

Cysteinyl-tRNA synthetase

CD44v:

CD44 variant

CDO1:

Cysteine dioxygenase type 1

CHOP:

C/EBP-homologous protein

CISD1:

CDGSH iron sulfur domain 1

c-Myb:

Cellular homolog

C-Myc:

Cellular myelocytomatosis oncogene

CN-A:

Cotylenin A

CoQ10:

Coenzyme Q10

CTH:

Cystathionine γ-lyase

Cul3:

Cullin-3

Cys:

Cysteine

Cys2:

Cystine

DAMPs:

Damage-associated molecular patterns

DDP4:

Dipeptidyl-peptidase-4

DHA:

Docosahexaenoic acid

DLBCL:

Diffuse large B-cell lymphoma

DMT1:

Divalent metal transporter 1

EGLN1:

Egl nine homolog 1

ELAVL1:

Embryonic lethal, abnormal vision, Drosophila-like 1

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

FADS2:

Fatty acid desaturase 2

FIN:

Ferroptosis inducing agents

Flt3:

Fms-like tyrosine kinase 3

FPN:

Ferroportin

FTH1:

Ferritin heavy chain 1

FTL:

Ferritin light chain

G3BP1:

Ras GTPase-activating protein-binding protein 1

GBM:

Glioblastoma multiforme

Gln:

Glutamine

GLS2:

Glutaminase 2

Glu:

Glutamate

GLUT1:

Glucose transporter 1

GOT1:

Glutamic-oxaloacetic transaminase 1

GPX4:

Glutathione peroxidase 4

GSC:

Glioblastoma stem cells

GSH:

Glutathione

HIF:

Hypoxia-inducible transcriptional factor

HNCs:

Head and neck cancers

HO-1:

Heme oxygenase-1

HSF1:

Heat shock factor-1

HSPB1:

Heat shock protein beta-1

IPP:

Isopentenyl pyrophosphate

IRE:

Iron-responsive element

IREB2:

Iron response element binding protein 2

Keap1 :

Keleh-like ECH-associated protein 1

LDL:

Low-density lipoprotein

LncRNA:

Long non-coding RNA

LPCAT3:

Lysophosphatidylcholine acyltransferase 3

LSH:

Lymphoid-specific helicase

MEK:

Ras-mitogen-activated protein kinase kinase

MON-P53:

Metal organic network-P53

MT-1G:

Metallothionein-1 g

MUC1-C:

Mucin 1 C-terminal

MVA:

Mevalonate

NCOA4:

Nuclear receptor coactivator 4

NFS1:

Cysteine desulfurase

NOX:

Nicotinamide adenine dinucleotide phosphate-oxidase

NQO1:

Quinone oxidoreductase-1

Nrf2:

Nuclear factor erythroid 2-related factor 2

PHKG2 :

Phosphorylase kinase gamma 2

PIK3C3:

Phosphatidylinositol 3-kinase catalytic subunit type 3

PL-PUFAs:

Phospholipid-polyunsaturated fatty acids

PtdIns3K :

Phosphatidylinositol 3-kinase

PUFAs:

Polyunsaturated fatty acids

PUMA:

P53 upregulated modulator of apoptosis

RB:

Retinoblastoma

ROS:

Reactive oxygen species

RRM:

RNA recognition motif

RSL3:

Ras-selective lethal small molecule 3

SAT1:

Spermidine/spermine N1-acetyltransferase 1

SCD1:

Stearoyl-CoA desaturase 1

Se:

Selenium

SLC1A5:

Solute carrier family 1 member 5

SLC3A2:

Solute carrier family 3 member 2

SLC7A11:

Solute carrier family 7 member 11

SOD1:

Superoxide dismutase 1

SQS:

Squalene synthase

STEAP3:

Six-transmembrane epithelial antigen of the prostate 3

TF:

Transferrin

TFR1:

Transferrin receptor 1

TICs:

Tumor-initiating cells

TP53:

Tumor suppressor P53

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

UPR:

Unfolded protein response

VDAC2/3:

Voltage-dependent anion channel 2/3

xCT:

System xc-

α-KG:

α-ketoglutarate

References

  1. Dixon SJ. Ferroptosis: bug or feature? Immunol Rev. 2017;277:150–7.

    Article  CAS  PubMed  Google Scholar 

  2. Yagoda N, Von RM, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447:864–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Yu H, Guo P, Xie X, Wang Y, Chen G. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med. 2017;21:648–57.

    Article  CAS  PubMed  Google Scholar 

  4. Latunde-Dada GO. Ferroptosis: role of lipid peroxidation, iron and ferritinophagy. Biochim Biophys Acta. 2017;1861(8):1893.

    Article  CAS  Google Scholar 

  5. Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016;73:2195–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23(3):369–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15:234–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fearnhead HO, Vandenabeele P, Vanden TB. How do we fit ferroptosis in the family of regulated cell death? Cell Death Differ. 2017;24:1991–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ueda S, Nakamura H, Masutani H, Sasada T, Yonehara S, Takabayashi A, et al. Redox regulation of caspase-3(-like) protease activity: regulatory roles of thioredoxin and cytochrome c. J Immunol. 1998;161:6689–95.

    CAS  PubMed  Google Scholar 

  11. Ye J, Zhang R, Wu F, Zhai L, Wang K, Xiao M, et al. Non-apoptotic cell death in malignant tumor cells and natural compounds. Cancer Lett. 2018;420:210–27.

    Article  CAS  PubMed  Google Scholar 

  12. Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 2017;20:1692–704.

    Article  CAS  PubMed  Google Scholar 

  13. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kaiser AM, Attardi LD. Deconstructing networks of p53-mediated tumor suppression in vivo. Cell Death Differ. 2018;25:93–103.

    Article  CAS  PubMed  Google Scholar 

  15. Tarangelo A, Magtanong L, Bieging-Rolett KT, Li Y, Ye J, Attardi LD, et al. p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep. 2018;22(3):569–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 2017;25:104–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Gnanapradeepan K, Basu S, Barnoud T, Budina-Kolomets A, Kung CP, Murphy ME. The p53 tumor suppressor in the control of metabolism and ferroptosis. Front Endocrinol. 2018;9:124.

    Article  Google Scholar 

  18. Ma S, Henson ES, Chen Y, Gibson SB. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis. 2016;7:e2307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C, et al. Ferroptosis: a novel anti-tumor action for cisplatin. Cancer Res Treat. 2018;50:445–60.

    Article  CAS  PubMed  Google Scholar 

  20. Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017;551:639–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fanzani A, Poli M. Iron, oxidative damage and ferroptosis in rhabdomyosarcoma. Int J Mol Sci. 2017;18:1718.

    Article  PubMed Central  CAS  Google Scholar 

  22. Song X, Zhu S, Chen P, Hou W, Wen Q, Liu J, et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system xc(−) activity. Curr Biol. 2018;28:2388–99.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kang R, Zhu S, Zeh HJ, Klionsky DJ, Tang D. BECN1 is a new driver of ferroptosis. Autophagy. 2018;14:2173–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mao C, Wang X, Liu Y, Wang M, Yan B, Jiang Y, et al. A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53. Cancer Res. 2018;78:3484–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang K, Wu L, Zhang P, Luo M, Du J, Gao T, et al. miR-9 regulates ferroptosis by targeting glutamic-oxaloacetic transaminase GOT1 in melanoma. Mol Carcinog. 2018;57:1566–76.

    Article  CAS  PubMed  Google Scholar 

  26. Luo M, Wu L, Zhang K, Wang H, Zhang T, Gutierrez L, et al. miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma. Cell Death Differ. 2018;25:1457–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu Y, Sun X, Song B, Qiu X, Zhao J. MiR-375/SLC7A11 axis regulates oral squamous cell carcinoma proliferation and invasion. Cancer Med. 2017;6:1686–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Drayton RM, Dudziec E, Peter S, Bertz S, Hartmann A, Bryant HE, et al. Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11. Clin Cancer Res. 2014;20:1990–2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu XX, Li XJ, Zhang B, Liang YJ, Zhou CX, Cao DX, et al. MicroRNA-26b is underexpressed in human breast cancer and induces cell apoptosis by targeting SLC7A11. FEBS Lett. 2011;585:1363–7.

    Article  CAS  PubMed  Google Scholar 

  30. Yuan J, Liu Z, Song R. Antisense lncRNA As-SLC7A11 suppresses epithelial ovarian cancer progression mainly by targeting SLC7A11. Pharmazie. 2017;72:402–7.

    CAS  PubMed  Google Scholar 

  31. Kabaria S, Choi DC, Chaudhuri AD, Jain MR, Li H, Junn E. MicroRNA-7 activates Nrf2 pathway by targeting Keap1 expression. Free Radic Biol Med. 2015;89:548–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Eades G, Yang M, Yao Y, Zhang Y, Zhou Q. miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells. J Biol Chem. 2011;286:40725–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yang M, Yao Y, Eades G, Zhang Y, Zhou Q. MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism. Breast Cancer Res Treat. 2011;129:983–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim JH, Lee KS, Lee DK, Kim J, Kwak SN, Ha KS, et al. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3. Antioxid Redox Signal. 2014;21:2469–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xu D, Zhu H, Wang C, Zhu X, Liu G, Chen C, et al. microRNA-455 targets cullin 3 to activate Nrf2 signaling and protect human osteoblasts from hydrogen peroxide. Oncotarget. 2017;8:59225–34.

    PubMed  PubMed Central  Google Scholar 

  36. Narasimhan M, Patel D, Vedpathak D, Rathinam M, Henderson G, Mahimainathan L. Identification of novel microRNAs in post-transcriptional control of Nrf2 expression and redox homeostasis in neuronal, SH-SY5Y cells. PLoS One. 2012;7:e51111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sangokoya C, Telen MJ, Chi JT. microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood. 2010;116:4338–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Singh B, Ronghe AM, Chatterjee A, Bhat NK, Bhat HK. MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis. Carcinogenesis. 2013;34:1165–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang Y, Tao X, Yin L, Xu L, Xu Y, Qi Y, et al. Protective effects of dioscin against cisplatin-induced nephrotoxicity via the microRNA-34a/sirtuin 1 signalling pathway. Br J Pharmacol. 2017;174:2512–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, et al. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res. 2012;40:7416–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Babu KR, Muckenthaler MU. miR-20a regulates expression of the iron exporter ferroportin in lung cancer. J Mol Med (Berl). 2016;94:347–59.

    Article  CAS  Google Scholar 

  42. Sangokoya C, Doss JF, Chi JT. Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin. PLoS Genet. 2013;9:e1003408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yoshioka Y, Kosaka N, Ochiya T, Kato T. Micromanaging iron homeostasis: hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins. J Biol Chem. 2012;287:34110–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kindrat I, Tryndyak V, de Conti A, Shpyleva S, Mudalige TK, Kobets T, et al. MicroRNA-152-mediated dysregulation of hepatic transferrin receptor 1 in liver carcinogenesis. Oncotarget. 2016;7:1276–87.

    Article  PubMed  Google Scholar 

  45. Shpyleva SI, Tryndyak VP, Kovalchuk O, Starlarddavenport A, Chekhun VF, Beland FA, et al. Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat. 2011;126:63–71.

    Article  CAS  PubMed  Google Scholar 

  46. Andolfo I, De Falco L, Asci R, Russo R, Colucci S, Gorrese M, et al. Regulation of divalent metal transporter 1 (DMT1) non-IRE isoform by the microRNA let-7d in erythroid cells. Haematologica. 2010;95:1244–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wu X, Zhi F, Lun W, Deng Q, Zhang W. Baicalin inhibits PDGF-BB-induced hepatic stellate cell proliferation, apoptosis, invasion, migration and activation via the miR-3595/ACSL4 axis. Int J Mol Med. 2018;41:1992–2002.

    PubMed  PubMed Central  Google Scholar 

  48. Cui M, Xiao ZL, Sun BD, Wang Y, Zheng MY, Ye LH, et al. Involvement of cholesterol in hepatitis B virus X protein-induced abnormal lipid metabolism of hepatoma cells via up-regulating miR-205-targeted ACSL4. Biochem Biophys Res Commun. 2014;445:651–5.

    Article  CAS  PubMed  Google Scholar 

  49. Peng Y, Xiang H, Chen C, Zheng R, Chai J, Peng J, et al. MiR-224 impairs adipocyte early differentiation and regulates fatty acid metabolism. Int J Biochem Cell Biol. 2013;45:1585–93.

    Article  CAS  PubMed  Google Scholar 

  50. Park S, Oh J, Kim M, Jin E-J. Bromelain effectively suppresses Kras-mutant colorectal cancer by stimulating ferroptosis. Anim Cells Syst. 2018;22:334–40.

    Article  CAS  Google Scholar 

  51. Zhang Y, Zheng S, Geng Y, Xue J, Wang Z, Xie X, et al. MicroRNA profiling of atrial fibrillation in canines: miR-206 modulates intrinsic cardiac autonomic nerve remodeling by regulating SOD1. PLoS One. 2015;10:e0122674.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Peng W, Zhu CF, Ma MZ, Gang C, Ming S, Zeng ZL, et al. Micro-RNA-155 is induced by K-Ras oncogenic signal and promotes ROS stress in pancreatic cancer. Oncotarget. 2015;6:21148–58.

    Google Scholar 

  53. Varga ZV, Kupai K, Szucs G, Gaspar R, Paloczi J, Farago N, et al. MicroRNA-25-dependent up-regulation of NADPH oxidase 4 (NOX4) mediates hypercholesterolemia-induced oxidative/nitrative stress and subsequent dysfunction in the heart. J Mol Cell Cardiol. 2013;62:111–21.

    Article  CAS  PubMed  Google Scholar 

  54. Kyrychenko S, Kyrychenko V, Badr MA, Ikeda Y, Sadoshima J, Shirokova N. Pivotal role of miR-448 in the development of ROS-induced cardiomyopathy. Cardiovasc Res. 2015;108:324–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zheng DW, Lei Q, Zhu JY, Fan JX, Li CX, Li C, et al. Switching apoptosis to ferroptosis: metal-organic network for high-efficiency anticancer therapy. Nano Lett. 2017;17:284–91.

    Article  CAS  PubMed  Google Scholar 

  56. Lee YS, Lee DH, Choudry HA, Bartlett DL, Lee YJ. Ferroptosis-induced endoplasmic reticulum stress: cross-talk between ferroptosis and apoptosis. Mol Cancer Res. 2018;16:1073–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hentze H, Schmitz I, Latta M, Krueger A, Krammer PH, Wendel A. Glutathione dependence of caspase-8 activation at the death-inducing signaling complex. J Biol Chem. 2002;277:5588–95.

    Article  CAS  PubMed  Google Scholar 

  58. Ma S, Dielschneider RF, Henson ES, Xiao W, Choquette TR, Blankstein AR, et al. Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells. PLoS One. 2017;12:e0182921.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Tang M, Chen Z, Wu D, Chen L. Ferritinophagy/ferroptosis: iron-related newcomers in human diseases. J Cell Physiol. 2018;233:9179–90.

    Article  CAS  PubMed  Google Scholar 

  60. Zhang Z, Yao Z, Wang L, Ding H, Shao J, Chen A, et al. Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells. Autophagy. 2018;14:2083–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Abdelmonsif DA, Sultan AS, El-Hadidy WF, Abdallah DM. Targeting AMPK, mTOR and β-catenin by combined metformin and aspirin therapy in HCC: an appraisal in Egyptian HCC patients. Mol Diagn Ther. 2017;22(5):1–13.

    Google Scholar 

  62. Yoshida GJ. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol. 2017;10(1):67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Lu BCX, Ying MD, He QJ, Cao J, Yang B. The role of ferroptosis in cancer development and treatment response. Front Pharmacol. 2018;8:992.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Buccarelli M, Marconi M, Pacioni S, De Pascalis I, D'Alessandris QG, Martini M, et al. Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis. Cell Death Dis. 2018;9:841.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Saintgermain E, Lian M, Vernier M. SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes. Aging. 2017;9(10):2137–62.

    Article  CAS  Google Scholar 

  67. Cotto-Rios XM, Gavathiotis E. Chemical genetics: unraveling cell death mysteries. Nat Chem Biol. 2016;12:470–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dong T, Liao D, Liu X, Lei X. Using small molecules to dissect non-apoptotic programmed cell death: necroptosis, Ferroptosis, and Pyroptosis. Chembiochem. 2015;16:2557–61.

    Article  CAS  PubMed  Google Scholar 

  69. Neitemeier S, Jelinek A, Laino V, Hoffmann L, Eisenbach I, Eying R, et al. BID links ferroptosis to mitochondrial cell death pathways. Redox Biol. 2017;12:558–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene. 2015;34:5617–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Louandre C, Marcq I, Bouhlal H, Lachaier E, Godin C, Saidak Z, et al. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett. 2015;356:971–7.

    Article  CAS  PubMed  Google Scholar 

  72. Nie J, Lin B, Zhou M, Wu L, Zheng T. Role of ferroptosis in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2018;144:2329–37.

    Article  CAS  PubMed  Google Scholar 

  73. Hao S, Yu J, He W, Huang Q, Zhao Y, Liang B, et al. Cysteine dioxygenase 1 mediates erastin-induced ferroptosis in human gastric cancer cells. Neoplasia. 2017;19:1022–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Masanori H, Hidekazu T, Hasan R, Maroof A, Yozo S, Li Y, et al. Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells. Oncotarget. 2016;7:11756–69.

    Google Scholar 

  75. Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc and thereby promotes tumor growth. Cancer Cell. 2011;19(3):387–400.

    Article  CAS  PubMed  Google Scholar 

  76. Basuli D, Tesfay L, Deng Z, Paul B, Yamamoto Y, Ning G, et al. Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene. 2017;36:4089–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Greenshields AL, Shepherd TG, Hoskin DW. Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate. Mol Carcinog. 2016;56:75–93.

    Article  PubMed  CAS  Google Scholar 

  78. Yang WS, Sriramaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kinowaki Y, Kurata M, Ishibashi S, Ikeda M, Tatsuzawa A, Yamamoto M, et al. Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma. Lab Investig. 2018;98:609–19.

    Article  CAS  PubMed  Google Scholar 

  80. Yu Y, Xie Y, Cao L, Yang L, Yang M, Lotze MT, et al. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol. 2015;2:e1054549.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Dolma S, Lessnick SL, Hahn WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003;3:285–96.

    Article  CAS  PubMed  Google Scholar 

  82. Yoshida GJ. Metabolic reprogramming: the emerging concept and associated therapeutic strategies. J Exp Clin Cancer Res. 2015;34(1):1–10.

    Article  CAS  Google Scholar 

  83. Okazaki F, Matsunaga N, Hamamura K, Suzuki K, Nakao T, Okazaki H, et al. Administering xCT inhibitors based on circadian clock improves antitumor effects. Cancer Res. 2017;77(23):0720.2017.

    Article  CAS  Google Scholar 

  84. Yoshida GJ. Emerging roles of Myc in stem cell biology and novel tumor therapies. J Exp Clin Cancer Res. 2018;37(1):173.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Toyokuni S, Ito F, Yamashita K, Okazaki Y, Akatsuka S. Iron and thiol redox signaling in cancer: an exquisite balance to escape ferroptosis. Free Radic Biol Med. 2017;108:610–26.

    Article  CAS  PubMed  Google Scholar 

  86. Yamaguchi Y, Kasukabe T, Kumakura S. Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis. Int J Oncol. 2018;52(3):1011–22.

    CAS  PubMed  Google Scholar 

  87. Roh JL, Kim EH, Jang HJ, Park JY, Shin D. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett. 2016;381:96–103.

    Article  CAS  PubMed  Google Scholar 

  88. Roh JL, Kim EH, Jang H, Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol. 2017;11:254–62.

    Article  CAS  PubMed  Google Scholar 

  89. Chen L, Li X, Liu L, Yu B, Xue Y, Liu Y. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function. Oncol Rep. 2015;33:1465–74.

    Article  CAS  PubMed  Google Scholar 

  90. Sehm T, Rauh M, Wiendieck K, Buchfelder M, Eyupoglu IY, Savaskan NE. Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis. Oncotarget. 2016;7:74630–47.

    PubMed  PubMed Central  Google Scholar 

  91. Lachaier E, Louandre C, Godin C, Saidak Z, Baert M, Diouf M, et al. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res. 2014;34:6417–22.

    CAS  PubMed  Google Scholar 

  92. Bai T, Wang S, Zhao Y, Zhu R, Wang W, Sun Y. Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2017;491:919–25.

    Article  CAS  PubMed  Google Scholar 

  93. Sauzay C, Louandre C, Bodeau S, Anglade F, Godin C, Saidak Z, et al. Protein biosynthesis, a target of sorafenib, interferes with the unfolded protein response (UPR) and ferroptosis in hepatocellular carcinoma cells. Oncotarget. 2018;9:8400–14.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Shen Z, Song J, Yung BC, Zhou Z, Wu A, Chen X. Emerging strategies of cancer therapy based on ferroptosis. Adv Mater. 2018;30:e1704007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Shaw AT, Winslow MM, Magendantz M, Ouyang C, Dowdle J, Subramanian A, et al. Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc Natl Acad Sci U S A. 2011;108:8773–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bazak R, Houri M, Achy SE, Hussein W, Refaat T. Passive targeting of nanoparticles to cancer: a comprehensive review of the literature. Mol Clin Oncol. 2014;2:904–8.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells—what challenges do they pose? Nat Rev Drug Discov. 2014;13:497–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Salt MB, Bandyopadhyay S, Mccormick F. Epithelial-to-mesenchymal transition rewires the molecular path to PI3K-dependent proliferation. Cancer Discovery. 2014;4:186–99.

    Article  CAS  PubMed  Google Scholar 

  99. Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20:1965.

    Article  CAS  PubMed  Google Scholar 

  100. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Ahern TP, Lash TL, Damkier P, Christiansen PM, Cronin-Fenton DP. Statins and breast cancer prognosis: evidence and opportunities. Lancet Oncol. 2014;15:e461–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Proneth B, Conrad M. Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ. 2019;26:14–24.

    Article  CAS  PubMed  Google Scholar 

  103. Garg AD, Agostinis P. Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses. Immunol Rev. 2017;280:126–48.

    Article  CAS  PubMed  Google Scholar 

  104. Kim SE, Zhang L, Ma K, Riegman M, Chen F, Ingold I, et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat Nanotechnol. 2016;11:977–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yoshida GJ. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol. 2017;10:67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Liu H, Schreiber SL, Stockwell BR. Targeting dependency on the GPX4 lipid peroxide repair pathway for cancer therapy. Biochemistry. 2018;57:2059–60.

    Article  CAS  PubMed  Google Scholar 

  107. Razaghi A, Heimann K, Schaeffer PM, Gibson SB. Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies. Apoptosis. 2018;23:93–112.

    Article  CAS  PubMed  Google Scholar 

  108. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife. 2014;3:e02523.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Eling N, Reuter L, Hazin J, Hamacherbrady A, Brady NR. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience. 2015;2:517–32.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Zhou L, Zhao B, Zhang L, Wang S, Dong D, Lv H, et al. Alterations in cellular iron metabolism provide more therapeutic opportunities for cancer. Int J Mol Sci. 2018;19:1545.

    Article  PubMed Central  CAS  Google Scholar 

  111. Sato M, Kusumi R, Hamashima S, Kobayashi S, Sasaki S, Komiyama Y, et al. The ferroptosis inducer erastin irreversibly inhibits system xc- and synergizes with cisplatin to increase cisplatin's cytotoxicity in cancer cells. Sci Rep. 2018;8:968.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Hinman A, Holst CR, Latham JC, Bruegger JJ, Ulas G, Mccusker KP, et al. Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS One. 2018;13:e0201369.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Jiang Y, Mao C, Yang R, Yan B, Shi Y, Liu X, et al. EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes. Theranostics. 2017;7:3293–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable

Funding

This work was supported by grants from the National Natural Science Foundation of China (81200366,81572281,81702278,81171841) and Province Natural Science Foundation of Hunan (No.14JJ6004) and the Key Subject Education Department of Hunan ([2012]594).

Availability of data and materials

The materials supporting the conclusion of this review have been included within the article.

Author information

Authors and Affiliations

Authors

Contributions

YHM and BL drafted the manuscript and prepared the figures and tables. JW, JCW, DH, CFZ, and CJD collected the references and participated in the discussion. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chaojun Duan or Bin Li.

Ethics declarations

Ethics approval and consent to participate

This is not applicable for this review.

Consent for publication

This is not applicable for this review.

Competing interests

The authors declare that they have no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mou, Y., Wang, J., Wu, J. et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol 12, 34 (2019). https://doi.org/10.1186/s13045-019-0720-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13045-019-0720-y

Keywords