Browse > Article
http://dx.doi.org/10.14348/molcells.2020.2197

Reduced EGFR Level in eIF2α Phosphorylation-Deficient Hepatocytes Is Responsible for Susceptibility to Oxidative Stress  

Kim, Mi-Jeong (School of Biological Sciences, University of Ulsan)
Choi, Woo-Gyun (School of Biological Sciences, University of Ulsan)
Ahn, Kyung-Ju (School of Biological Sciences, University of Ulsan)
Chae, In Gyeong (School of Biological Sciences, University of Ulsan)
Yu, Rina (Department of Food Science and Nutrition, University of Ulsan)
Back, Sung Hoon (School of Biological Sciences, University of Ulsan)
Publication Information
Molecules and Cells / v.43, no.3, 2020 , pp. 264-275 More about this Journal
Abstract
Reactive oxygen species (ROS) play a significant role in intracellular signaling and regulation, particularly when they are maintained at physiologic levels. However, excess ROS can cause cell damage and induce cell death. We recently reported that eIF2α phosphorylation protects hepatocytes from oxidative stress and liver fibrosis induced by fructose metabolism. Here, we found that hepatocyte-specific eIF2α phosphorylation-deficient mice have significantly reduced expression of the epidermal growth factor receptor (EGFR) and altered EGFR-mediated signaling pathways. EGFR-mediated signaling pathways are important for cell proliferation, differentiation, and survival in many tissues and cell types. Therefore, we studied whether the reduced amount of EGFR is responsible for the eIF2α phosphorylation-deficient hepatocytes' vulnerability to oxidative stress. ROS such as hydrogen peroxide and superoxides induce both EGFR tyrosine phosphorylation and eIF2α phosphorylation. eIF2α phosphorylation-deficient primary hepatocytes, or EGFR knockdown cells, have decreased ROS scavenging ability compared to normal cells. Therefore, these cells are particularly susceptible to oxidative stress. However, overexpression of EGFR in these eIF2α phosphorylation-deficient primary hepatocytes increased ROS scavenging ability and alleviated ROS-mediated cell death. Therefore, we hypothesize that the reduced EGFR level in eIF2α phosphorylation-deficient hepatocytes is one of critical factors responsible for their susceptibility to oxidative stress.
Keywords
$eIF2{\alpha}$ phosphorylation; epidermal growth factor receptor; hydrogen peroxide; menadione; reactive oxygen species;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Orcutt, K.P., Parsons, A.D., Sibenaller, Z.A., Scarbrough, P.M., Zhu, Y., Sobhakumari, A., Wilke, W.W., Kalen, A.L., Goswami, P., Miller, F.J., Jr., et al. (2011). Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4. Cancer Res. 71, 3932-3940.   DOI
2 Ostrowski, J., Woszczynski, M., Kowalczyk, P., Trzeciak, L., Hennig, E., and Bomsztyk, K. (2000). Treatment of mice with EGF and orthovanadate activates cytoplasmic and nuclear MAPK, p70S6k, and p90rsk in the liver. J. Hepatol. 32, 965-974.   DOI
3 Paech, F., Bouitbir, J., and Krahenbuhl, S. (2017). Hepatocellular toxicity associated with tyrosine kinase inhibitors: mitochondrial damage and inhibition of glycolysis. Front. Pharmacol. 8, 367.   DOI
4 Paulsen, C.E., Truong, T.H., Garcia, F.J., Homann, A., Gupta, V., Leonard, S.E., and Carroll, K.S. (2011). Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity. Nat. Chem. Biol. 8, 57-64.   DOI
5 Proud, C.G. (2005). eIF2 and the control of cell physiology. Semin. Cell Dev. Biol. 16, 3-12.   DOI
6 Quesnelle, K.M., Boehm, A.L., and Grandis, J.R. (2007). STAT-mediated EGFR signaling in cancer. J. Cell. Biochem. 102, 311-319.   DOI
7 Rajesh, K., Krishnamoorthy, J., Kazimierczak, U., Tenkerian, C., Papadakis, A.I., Wang, S., Huang, S., and Koromilas, A.E. (2015). Phosphorylation of the translation initiation factor eIF2alpha at serine 51 determines the cell fate decisions of Akt in response to oxidative stress. Cell Death Dis. 6, e1591.   DOI
8 Berasain, C. and Avila, M.A. (2014). The EGFR signalling system in the liver: from hepatoprotection to hepatocarcinogenesis. J. Gastroenterol. 49, 9-23.   DOI
9 Abdelmohsen, K., Gerber, P.A., von Montfort, C., Sies, H., and Klotz, L.O. (2003). Epidermal growth factor receptor is a common mediator of quinone-induced signaling leading to phosphorylation of connexin-43: role of glutathione and tyrosine phosphatases. J. Biol. Chem. 278, 38360-38367.   DOI
10 Back, S.H., Scheuner, D., Han, J., Song, B., Ribick, M., Wang, J., Gildersleeve, R.D., Pennathur, S., and Kaufman, R.J. (2009). Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metab. 10, 13-26.   DOI
11 Brunet, A., Bonni, A., Zigmond, M.J., Lin, M.Z., Juo, P., Hu, L.S., Anderson, M.J., Arden, K.C., Blenis, J., and Greenberg, M.E. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868.   DOI
12 Carballo, M., Conde, M., El Bekay, R., Martin-Nieto, J., Camacho, M.J., Monteseirin, J., Conde, J., Bedoya, F.J., and Sobrino, F. (1999). Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes. J. Biol. Chem. 274, 17580-17586.   DOI
13 Carpenter, G. and Cohen, S. (1990). Epidermal growth factor. J. Biol. Chem. 265, 7709-7712.   DOI
14 Sato, K. (2013). Cellular functions regulated by phosphorylation of EGFR on Tyr845. Int. J. Mol. Sci. 14, 10761-10790.   DOI
15 Rakhit, A., Pantze, M.P., Fettner, S., Jones, H.M., Charoin, J.E., Riek, M., Lum, B.L., and Hamilton, M. (2008). The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition. Eur. J. Clin. Pharmacol. 64, 31-41.   DOI
16 Rodriguez-Fragoso, L., Melendez, K., Hudson, L.G., Lauer, F.T., and Burchiel, S.W. (2009). EGF-receptor phosphorylation and downstream signaling are activated by benzo[a]pyrene 3,6-quinone and benzo[a]pyrene 1,6-quinone in human mammary epithelial cells. Toxicol. Appl. Pharmacol. 235, 321-328.   DOI
17 Sadidi, M., Lentz, S.I., and Feldman, E.L. (2009). Hydrogen peroxide-induced Akt phosphorylation regulates Bax activation. Biochimie 91, 577-585.   DOI
18 Schneider, M.R. and Wolf, E. (2009). The epidermal growth factor receptor ligands at a glance. J. Cell. Physiol. 218, 460-466.   DOI
19 Schreier, B., Rabe, S., Schneider, B., Bretschneider, M., Rupp, S., Ruhs, S., Neumann, J., Rueckschloss, U., Sibilia, M., Gotthardt, M., et al. (2013). Loss of epidermal growth factor receptor in vascular smooth muscle cells and cardiomyocytes causes arterial hypotension and cardiac hypertrophy. Hypertension 61, 333-340.   DOI
20 Sham, D., Wesley, U.V., Hristova, M., and van der Vliet, A. (2013). ATP-mediated transactivation of the epidermal growth factor receptor in airway epithelial cells involves DUOX1-dependent oxidation of Src and ADAM17. PLoS One 8, e54391.   DOI
21 Sonenberg, N. and Hinnebusch, A.G. (2009). Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731-745.   DOI
22 Citri, A. and Yarden, Y. (2006). EGF-ERBB signalling: towards the systems level. Nat. Rev. Mol. Cell Biol. 7, 505-516.   DOI
23 Chiarugi, P. and Buricchi, F. (2007). Protein tyrosine phosphorylation and reversible oxidation: two cross-talking posttranslation modifications. Antioxid. Redox Signal. 9, 1-24.   DOI
24 Choi, W.G., Han, J., Kim, J.H., Kim, M.J., Park, J.W., Song, B., Cha, H.J., Choi, H.S., Chung, H.T., Lee, I.K., et al. (2017). eIF2alpha phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet. Nutr. Metab. (Lond.) 14, 48.   DOI
25 Chowdhry, S., Zhang, Y., McMahon, M., Sutherland, C., Cuadrado, A., and Hayes, J.D. (2013). Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32, 3765-3781.   DOI
26 Fan, Q.W., Cheng, C.K., Gustafson, W.C., Charron, E., Zipper, P., Wong, R.A., Chen, J., Lau, J., Knobbe-Thomsen, C., Weller, M., et al. (2013). EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell 24, 438-449.   DOI
27 Filosto, S., Khan, E.M., Tognon, E., Becker, C., Ashfaq, M., Ravid, T., and Goldkorn, T. (2011). EGF receptor exposed to oxidative stress acquires abnormal phosphorylation and aberrant activated conformation that impairs canonical dimerization. PLoS One 6, e23240.   DOI
28 Gamou, S. and Shimizu, N. (1995). Hydrogen peroxide preferentially enhances the tyrosine phosphorylation of epidermal growth factor receptor. FEBS Lett. 357, 161-164.   DOI
29 Goldkorn, T., Balaban, N., Matsukuma, K., Chea, V., Gould, R., Last, J., Chan, C., and Chavez, C. (1998). EGF-Receptor phosphorylation and signaling are targeted by H2O2 redox stress. Am. J. Respir. Cell Mol. Biol. 19, 786-798.   DOI
30 Wang, X., McCullough, K.D., Franke, T.F., and Holbrook, N.J. (2000). Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J. Biol. Chem. 275, 14624-14631.   DOI
31 Wang, X.T., McCullough, K.D., Wang, X.J., Carpenter, G., and Holbrook, N.J. (2001). Oxidative stress-induced phospholipase C-gamma 1 activation enhances cell survival. J. Biol. Chem. 276, 28364-28371.   DOI
32 Wek, R.C., Jiang, H.Y., and Anthony, T.G. (2006). Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34, 7-11.   DOI
33 Weng, M.S., Chang, J.H., Hung, W.Y., Yang, Y.C., and Chien, M.H. (2018). The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance. J. Exp. Clin. Cancer Res. 37, 61.   DOI
34 Haouzi, D., Lekehal, M., Moreau, A., Moulis, C., Feldmann, G., Robin, M.A., Letteron, P., Fau, D., and Pessayre, D. (2000). Cytochrome P450-generated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes. Hepatology 32, 303-311.   DOI
35 Guren, T.K., Odegard, J., Abrahamsen, H., Thoresen, G.H., Susa, M., Andersson, Y., Ostby, E., and Christoffersen, T. (2003). EGF receptor-mediated, c-Src-dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes. J. Cell. Physiol. 196, 113-123.   DOI
36 Hagenbuchner, J., Kuznetsov, A., Hermann, M., Hausott, B., Obexer, P., and Ausserlechner, M.J. (2012). FOXO3-induced reactive oxygen species are regulated by BCL2L11 (Bim) and SESN3. J. Cell Sci. 125, 1191-1203.   DOI
37 Han, J., Back, S.H., Hur, J., Lin, Y.H., Gildersleeve, R., Shan, J., Yuan, C.L., Krokowski, D., Wang, S., Hatzoglou, M., et al. (2013). ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481-490.   DOI
38 Heppner, D.E. and van der Vliet, A. (2016). Redox-dependent regulation of epidermal growth factor receptor signaling. Redox Biol. 8, 24-27.   DOI
39 Jorissen, R.N., Walker, F., Pouliot, N., Garrett, T.P., Ward, C.W., and Burgess, A.W. (2003). Epidermal growth factor receptor: mechanisms of activation and signalling. Exp. Cell Res. 284, 31-53.   DOI
40 Kim, D., Dai, J., Fai, L.Y., Yao, H., Son, Y.O., Wang, L., Pratheeshkumar, P., Kondo, K., Shi, X., and Zhang, Z. (2015). Constitutive activation of epidermal growth factor receptor promotes tumorigenesis of Cr(VI)-transformed cells through decreased reactive oxygen species and apoptosis resistance development. J. Biol. Chem. 290, 2213-2224.   DOI
41 Lewerenz, J. and Maher, P. (2009). Basal levels of eIF2alpha phosphorylation determine cellular antioxidant status by regulating ATF4 and xCT expression. J. Biol. Chem. 284, 1106-1115.   DOI
42 Kim, M.K., Yee, J., Cho, Y.S., Jang, H.W., Han, J.M., and Gwak, H.S. (2018). Risk factors for erlotinib-induced hepatotoxicity: a retrospective follow-up study. BMC Cancer 18, 988.   DOI
43 Kitade, M., Factor, V.M., Andersen, J.B., Tomokuni, A., Kaji, K., Akita, H., Holczbauer, A., Seo, D., Marquardt, J.U., Conner, E.A., et al. (2013). Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling. Genes Dev. 27, 1706-1717.   DOI
44 Lee, S.R., Kwon, K.S., Kim, S.R., and Rhee, S.G. (1998). Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J. Biol. Chem. 273, 15366-15372.   DOI
45 Li, J., Zhao, M., He, P., Hidalgo, M., and Baker, S.D. (2007). Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin. Cancer Res. 13, 3731-3737.   DOI
46 Liebmann, C. (2011). EGF receptor activation by GPCRs: an universal pathway reveals different versions. Mol. Cell. Endocrinol. 331, 222-231.   DOI
47 Liu, L., Wise, D.R., Diehl, J.A., and Simon, M.C. (2008). Hypoxic reactive oxygen species regulate the integrated stress response and cell survival. J. Biol. Chem. 283, 31153-31162.   DOI
48 Ma, Q. (2013). Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 53, 401-426.   DOI
49 Miklossy, G., Hilliard, T.S., and Turkson, J. (2013). Therapeutic modulators of STAT signalling for human diseases. Nat. Rev. Drug Discov. 12, 611-629.   DOI
50 Morita, M., Matsuzaki, H., Yamamoto, T., Fukami, Y., and Kikkawa, U. (2008). Epidermal growth factor receptor phosphorylates protein kinase C {delta} at Tyr332 to form a trimeric complex with p66Shc in the H2O2-stimulated cells. J. Biochem. 143, 31-38.
51 Musallam, L., Ethier, C., Haddad, P.S., and Bilodeau, M. (2001). Role of EGF receptor tyrosine kinase activity in antiapoptotic effect of EGF on mouse hepatocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G1360-G1369.   DOI
52 Oh, H.Y., Namkoong, S., Lee, S.J., Por, E., Kim, C.K., Billiar, T.R., Han, J.A., Ha, K.S., Chung, H.T., Kwon, Y.G., et al. (2006). Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP. Cell Death Differ. 13, 512-523.   DOI