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http://dx.doi.org/10.5090/kjtcs.2017.50.3.153

The Antitumor Effect of C-terminus of Hsp70-Interacting Protein via Degradation of c-Met in Small Cell Lung Cancer  

Cho, Sung Ho (Department of Thoracic and Cardiovascular Surgery, Kosin University Gospel Hospital, Kosin University College of Medicine)
Kim, Jong In (Department of Thoracic and Cardiovascular Surgery, Kosin University Gospel Hospital, Kosin University College of Medicine)
Kim, Hyun Su (Department of Thoracic and Cardiovascular Surgery, Kosin University Gospel Hospital, Kosin University College of Medicine)
Park, Sung Dal (Department of Thoracic and Cardiovascular Surgery, Kosin University Gospel Hospital, Kosin University College of Medicine)
Jang, Kang Won (Yonsei Research Institute of Aging Science, Yonsei University)
Publication Information
Journal of Chest Surgery / v.50, no.3, 2017 , pp. 153-162 More about this Journal
Abstract
Background: The mesenchymal-epithelial transition factor (MET) receptor can be overexpressed in solid tumors, including small cell lung cancer (SCLC). However, the molecular mechanism regulating MET stability and turnover in SCLC remains undefined. One potential mechanism of MET regulation involves the C-terminus of Hsp70-interacting protein (CHIP), which targets heat shock protein 90-interacting proteins for ubiquitination and proteasomal degradation. In the present study, we investigated the functional effects of CHIP expression on MET regulation and the control of SCLC cell apoptosis and invasion. Methods: To evaluate the expression of CHIP and c-Met, which is a protein that in humans is encoded by the MET gene (the MET proto-oncogene), we examined the expression pattern of c-Met and CHIP in SCLC cell lines by western blotting. To investigate whether CHIP overexpression reduced cell proliferation and invasive activity in SCLC cell lines, we transfected cells with CHIP and performed a cell viability assay and cellular apoptosis assays. Results: We found an inverse relationship between the expression of CHIP and MET in SCLC cell lines (n=5). CHIP destabilized the endogenous MET receptor in SCLC cell lines, indicating an essential role for CHIP in the regulation of MET degradation. In addition, CHIP inhibited MET-dependent pathways, and invasion, cell growth, and apoptosis were reduced by CHIP overexpression in SCLC cell lines. Conclusion: C HIP is capable of regulating SCLC cell apoptosis and invasion by inhibiting MET-mediated cytoskeletal and cell survival pathways in NCI-H69 cells. CHIP suppresses MET-dependent signaling, and regulates MET-mediated SCLC motility.
Keywords
Lung neoplasms; Small cell lung carcinoma; C-terminus of Hsp70-interacting protein; Mesenchymal-epithelial transition factor;
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1 Qian SB, McDonough H, Boellmann F, Cyr DM, Patterson C. CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature 2006;440:551-5.   DOI
2 Jang KW, Lee JE, Kim SY, et al. The C-terminus of Hsp70- interacting protein promotes Met receptor degradation. J Thorac Oncol 2011;6:679-87.   DOI
3 Kajiro M, Hirota R, Nakajima Y, et al. The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways. Nat Cell Biol 2009;11:312-9.   DOI
4 Wang S, Wu X, Zhang J, et al. CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer. Gut 2013;62:496-508.   DOI
5 Morgan MA, Parsels LA, Kollar LE, Normolle DP, Maybaum J, Lawrence TS. The combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation in pancreatic cancer. Clin Cancer Res 2008;14:5142-9.   DOI
6 Comoglio PM, Boccaccio C. Scatter factors and invasive growth. Semin Cancer Biol 2001;11:153-65.   DOI
7 Connell P, Ballinger CA, Jiang J, et al. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 2001;3:93-6.   DOI
8 Demand J, Alberti S, Patterson C, Hohfeld J. Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr Biol 2001; 11:1569-77.   DOI
9 Zhou P, Fernandes N, Dodge IL, et al. ErbB2 degradation mediated by the co-chaperone protein CHIP. J Biol Chem 2003;278:13829-37.   DOI
10 Wang T, Yang J, Xu J, et al. CHIP is a novel tumor suppressor in pancreatic cancer through targeting EGFR. Oncotarget 2014;5:1969-86.
11 Kuba K, Matsumoto K, Date K, Shimura H, Tanaka M, Nakamura T. HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Res 2000;60:6737-43.
12 Ma PC, Tretiakova MS, Nallasura V, Jagadeeswaran R, Husain AN, Salgia R. Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion. Br J Cancer 2007;97: 368-77.   DOI
13 Zhang YH, Wei W, Xu H, Wang YY, Wu WX. Inducing effects of hepatocyte growth factor on the expression of vascular endothelial growth factor in human colorectal carcinoma cells through MEK and PI3K signaling pathways. Chin Med J (Engl) 2007;120:743-8.
14 Sawada K, Radjabi AR, Shinomiya N, et al. c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Res 2007;67:1670-9.   DOI
15 Di Renzo MF, Narsimhan RP, Olivero M, et al. Expression of the Met/HGF receptor in normal and neoplastic human tissues. Oncogene 1991;6:1997-2003.
16 Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96.   DOI
17 Jackman DM, Johnson BE. Small-cell lung cancer. Lancet 2005;366:1385-96.   DOI
18 Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991;251:802-4.   DOI
19 Ma PC, Kijima T, Maulik G, et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res 2003;63:6272-81.
20 Lengyel E, Prechtel D, Resau JH, et al. C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer 2005;113:678-82.   DOI
21 Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG. The role of STATs in lung carcinogenesis: an emerging target for novel therapeutics. J Mol Med (Berl) 2007;85: 427-36.   DOI
22 Kim SJ, Johnson M, Koterba K, Herynk MH, Uehara H, Gallick GE. Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model. Clin Cancer Res 2003;9:5161-70.
23 Peschard P, Ishiyama N, Lin T, Lipkowitz S, Park M. A conserved DpYR motif in the juxtamembrane domain of the Met receptor family forms an atypical c-Cbl/Cbl-b tyrosine kinase binding domain binding site required for suppression of oncogenic activation. J Biol Chem 2004; 279:29565-71.   DOI
24 Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39.   DOI
25 Zhang M, Windheim M, Roe SM, et al. Chaperoned ubiquitylation: crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex. Mol Cell 2005;20:525-38.   DOI
26 Maulik G, Kijima T, Ma PC, et al. Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res 2002;8:620-7.
27 Hammond DE, Urbe S, Vande Woude GF, Clague MJ. Down-regulation of MET, the receptor for hepatocyte growth factor. Oncogene 2001;20:2761-70.   DOI
28 Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003;4:915-25.   DOI
29 Wang S, Pashtan I, Tsutsumi S, Xu W, Neckers L. Cancer cells harboring MET gene amplification activate alternative signaling pathways to escape MET inhibition but remain sensitive to Hsp90 inhibitors. Cell Cycle 2009;8: 2050-6.   DOI
30 McDonough H, Patterson C. CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 2003;8:303-8.   DOI