Cancer cachexia: molecular mechanisms and treatment strategies

Setiawan, Tania; Sari, Ita Novita; Wijaya, Yoseph Toni; Julianto, Nadya Marcelina; Muhammad, Jabir Aliyu; Lee, Hyeok; Chae, Ji Heon; Kwon, Hyog Young

doi:10.1186/s13045-023-01454-0

Journal of Hematology & Oncology

Table 1 Major component and deregulated signaling pathways in cancer cachexia

From: Cancer cachexia: molecular mechanisms and treatment strategies

Pathway	Signaling	Regulator	Signaling implicated	Function	Expression	References
Anabolic	mTOR	mTORC1	S6 kinase phosphorylation	Regulates protein synthesis	Decreased	[11, 123, 124]
			FGF21 induction and mitochondrial biogenesis	Regulates muscle growth and positively associated with muscle mass
		mTORC2	Phosphorylates PKB/Akt on Ser473	Regulates glucose and lipid homeostasis		[11, 124]
	Insulin and IGF1-AKT	IGF1	mTOR activator	Regulates protein synthesis and degradation, cellular proliferation, glucose uptake, and energy production		[11, 132]
			P13K/AKT activation			[150]
			Suppression of MuRF1 and Atrogin-1			[150]
		AKT	Inhibits the NF-kB pathway and the FoxO protein	Regulates muscle growth		[137]
		Plakoglobin	Activation of PI3K-AKT-FoxO signaling	Controls muscle growth and metabolism		[151]
	BMP/Smad1/5/8	BMP	Smad1/5/8 phosphorylation	Positive regulator of muscle mass growth		[154, 155]
		BMP7	Activation of Smad1/5/8 signaling	Regulates protein synthesis		[157]
Catabolic	Ubiquitin–proteasome system	Myostatin	Represses the Akt/mTOR pathway; activates SMAD2 and SMAD3 transcription; upregulates MuRF1, MAFbx/Atrogin1, and FOXO expression	Positive regulator of protein breakdown	Increased	[173, 174, 177, 180]
		Activin A		Positive regulator of protein breakdown		[173, 177, 180]
			Induces BMP inhibitor Noggin expression	BMP activity inhibitor in muscle fibers and motor nerves		[156]
		Smad2/3	Regulates myostatin and activin A expression	Negative regulators of muscle growth		[154, 155]
	NF-κB	NF-κB	IGF1 inhibitor	Regulator of muscle cell death and specific transcriptional regulation		[189, 190]
			Suppresses MyoD expression
			Increases MuRF1 expression	Positive regulators of proteolysis of skeletal muscle proteins		[306]
			iNOS/NO pathway regulator	Negative regulator of skeletal muscle growth		[191, 307]
		NIK	increases the levels of atrophy markers	Negative regulator of skeletal muscle growth		[306]
	Inflammatory cytokines	TNF-α	NF-κB activation; involved in the ubiquitin conjugation and proteasomal degradation of iKb	Positive regulators of proteolysis of skeletal muscle proteins		[189, 190, 197]
			induces the expression of ubiquitin genes in the UPS and activates the p38 MAPK pathway	Stimulates both reactive oxygen production and general activity of the ubiquitin-conjugating pathway		[164]
	IL-6-JAK-STAT3	STAT3	Stimulates mitochondrial respiration	Promotes myogenic lineage progression in muscle stem cells		[198,199,200]
			Increase expression of myostatin, MAFbx, and MURF1	Regulates skeletal muscle mass in myofibers		[207, 208]
			Activation of the IκB kinase (IKK)/NF-κB signaling pathway	Positive regulators of apoptosis		[307]
			Stimulates C/EBPδ expression and activity	Positive regulators of apoptosis		[207, 208]
		IL-6	Induces STAT3 phosphorylation	Positive regulators skeletal muscle proteolysis		[162, 204, 205]
			Activation of IL3			[[206]
			AMPK activation and suppression of mTORC1 activation			[133]
			Induces BMP inhibitor Noggin expression	Negative regulator of BMP activity in muscle fibers and motor nerves		[156]
	Cell autophagy/lysosomal pathway (ALP)	BNIP3A	Autophagy mediators	Selective elimination of damaged organelles and degradation of misfolded proteins		[108, 112]
		LC3B	Autophagy mediators	Driver of skeletal muscle proteolysis		[111, 112]
		FOXO3	Main transcription factor that induces autophagy	Regulates the expression of autophagy genes		[99]
			Reduces IGF1/PI3K/AKT signaling pathway activity via mTOR and transcriptional dependent mechanisms	Positive regulator of ALP		[99]
		ATG7	Regulator of p38 MAPK pathway	Positive regulator of ALP		[107]
	Ca2 + -activated degradation	Calcium	Regulates the binding of calpastatin to calpain	Calpain activity inhibitor		[117]
			Regulation of glucocorticoid	Driver of skeletal muscle proteolysis		[119]
		Calpains	Cleaves myofibrillar proteins	Disrupt sarcomeres		[118, 120, 171]
		Proteolysis-inducing factor (PIF)	Induces a high accumulation of Ca²⁺	Positive regulator Ca²⁺-dependent degradation system		[122]

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ISSN: 1756-8722

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