High expression of neuroguidin increases the sensitivity of acute myeloid leukemia cells to chemotherapeutic drugs
- Kejun Chen†1,
- Shuqing Lü†1Email author,
- Hui Cheng†1,
- Gusheng Tang1,
- Min Liu1,
- Hong Zhou1 and
- Jianmin Wang1Email author
© Chen et al.; licensee BioMed Central. 2015
Received: 17 December 2014
Accepted: 8 January 2015
Published: 19 February 2015
Neuroguidin (NGDN) is a eukaryotic translation initiation factor 4E binding protein. The purpose of this study was to clarify the function of NGDN and its possible mechanism of action in human myeloid leukemia cells. Proliferation inhibition and apoptosis in NGDN over-expressing myeloid multidrug-resistant leukemia cells (K562/A02-NGDN) was significantly higher than in control K562/A02 cells following treatment with vincristine, etoposide, and epirubicin, indicating that NGDN over-expression can increase the sensitivity of multidrug-resistant leukemia cells to chemotherapeutic drugs. Furthermore, NGDN knock-down in K562/A02 cells resulted in the activation of multiple tumor-related signaling pathways, especially the mammalian target of rapamycin (mTOR) pathway.
We previously reported the expression of some genes with unknown functions in myeloid leukemia cell lines and primary leukemia cells from clinical patients [1-3], one of which was homologous to neuroguidin (NGDN) . Jung and colleagues confirmed that NGDN has a similar structure and function to eukaryotic translation initiation factor 4E (eIF4E) binding proteins , which are known to inhibit the cap-dependent protein translation as negative regulators of eIF4E and are involved in tumor cell proliferation, survival, and apoptosis [5-9]. Low expression and high phosphorylation of eIF4E binding protein 1 (4E-BP1) is associated with poor prognosis and tumor invasion . High expression of 4E-BPs enhances tumor cell sensitivity to chemotherapeutic drugs and is associated with favorable clinical prognosis [11-13]. In this study, the effect of NGDN and its mechanism of action in human myeloid leukemia cells were investigated.
Effects of NGDN over-expression on proliferation and apoptosis in multidrug-resistant leukemia cell line K562/A02
Effect of NGDN knock-down in K562/A02 cells
The main genes up-regulated in NGDN knock-down leukemia cells K562/A02-KD compared with negative control cells K562/A02-NC (n = 3, P < 0.05)
Relative mRNA expression level (K562/A02-KD/K562/A02-NC)
Extracellular signal gene
Signal transduction pathway gene
Transcription factor gene
Cell invasion and metastasis-related gene
Overall, the results of this study in vitro confirmed that NGDN over-expression can increase the sensitivity of human myeloid multidrug-resistant leukemia cells to chemotherapeutic drugs, indicating that the high expression of NGDN may be a favorable prognostic factor for patients with acute myeloid leukemia [see Additional file 1]. The specific mechanism of action of NGDN in leukemia cells requires further study.
This work is supported by grants from the National Natural Science Foundation of China [grant numbers 30873042, 81100361 to S.L.].
- Lü SQ, Xu XP, Xia F, Wang JM. Differential gene expression analysis of human leukemic cell line with different tumorigenic potentials in nude mice. Zhonghua Zhong Liu Za Zhi. 2004;26:196–200.PubMedGoogle Scholar
- Chen L, Xu XP, Wang JM, Li Y, Xu H, Lü SQ, et al. Spectrum of gene expression of a multi-drug resistant leukemia cell line with high tumorigenicity in nude mice. Zhonghua Zhong Liu Za Zhi. 2005;27:196–200.PubMedGoogle Scholar
- Chen L, Wang JM, Xu XP, Li Y, Xu H, Ju XP, et al. A pilot study of spectrum of gene expression of acute leukemia. Zhonghua Yi Xue Za Zhi. 2005;85:1089–92.PubMedGoogle Scholar
- Jung MY, Lorenz L, Richter JD. Translational control by neuroguidin, a eukaryotic initiation factor 4E and CPEB binding protein. Mol Cell Biol. 2006;26:4277–87.View ArticlePubMed CentralPubMedGoogle Scholar
- Richter JD, Sonenberg N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature. 2005;433:477–80.View ArticlePubMedGoogle Scholar
- Dilling MB, Germain GS, Dudkin L, Jayaraman AL, Zhang X, Harwood FC, et al. 4E-binding proteins, the suppressors of eukaryotic initiation factor 4E, are down-regulated in cells with acquired or intrinsic resistance to rapamycin. J Biol Chem. 2002;277:13907–17.View ArticlePubMedGoogle Scholar
- Provenzani A, Fronza R, Loreni F, Pascale A, Amadio M, Quattrone A. Global alterations in mRNA polysomal recruitment in a cell model of colorectal cancer progression to metastasis. Carcinogenesis. 2006;27:1323–33.View ArticlePubMedGoogle Scholar
- Coleman LJ, Peter MB, Teall TJ, Brannan RA, Hanby AM, Honarpisheh H, et al. Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity. Br J Cancer. 2009;100:1393–9.View ArticlePubMed CentralPubMedGoogle Scholar
- Yuan R, Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol. 2009;2:45.View ArticlePubMed CentralPubMedGoogle Scholar
- Castellvi J, Garcia A, Rojo F, Ruiz-Marcellan C, Gil A, Baselga J, et al. Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer. 2006;107:1801–11.View ArticlePubMedGoogle Scholar
- Clemens MJ, Elia A, Morley SJ. Requirement for the binding proteins for the synergistic down-regulation of protein synthesis by hypertonic conditions and mTOR inhibition. PLoS ONE. 2013;8:e71138.View ArticlePubMed CentralPubMedGoogle Scholar
- Chakravarthy R, Clemens MJ, Pirianov G, Perdios N, Mudan S, Cartwright JE, et al. Role of the eIF4E binding protein 4E-BP1 in regulation of the sensitivity of human pancreatic cancer cells to TRAIL and celastrol-induced apoptosis. Biol Cell. 2013;105(9):414–29.View ArticlePubMedGoogle Scholar
- Zhu HL, Xie SM, Fang M, Zhang JJ, Weng ZP, Zhong XY. 4E-BP1 regulates the sensitivity of human glioma cells to chemotherapy through PI3K/Akt/mTOR-independent pathway. Neuropathology. 2014;34(3):227–35.View ArticlePubMedGoogle Scholar
- Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005;65(16):7052–8.View ArticlePubMedGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.