Cisplatin-induced senescence in ovarian cancer cells is mediated by GRP78

Li,Wei; Wang,Wei; Dong,Hong; Li,Yan; Li,Li; Han,Linfei; Han,Zhiqiang; Wang,Shixuan; Ma,Ding; Wang,Hui

doi:10.3892/or.2014.3147

Cisplatin-induced senescence in ovarian cancer cells is mediated by GRP78

Authors:
- Wei Li
- Wei Wang
- Hong Dong
- Yan Li
- Li Li
- Linfei Han
- Zhiqiang Han
- Shixuan Wang
- Ding Ma
- Hui Wang
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Affiliations: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P.R. China, Shanghai First Maternity and Infant Health Hospital, Tongji University, Shanghai 200040, P.R. China
Published online on: April 23, 2014 https://doi.org/10.3892/or.2014.3147
Pages: 2525-2534

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Abstract

Glucose-regulated protein 78 (GRP78), the most abundant and well-characterized glucose-regulated protein, is a major stress-inducible chaperone localized to the endoplasmic reticulum (ER). The purpose of the present study was to investigate the mechanisms of GRP78 involved in the senescence sensitivity of ovarian cancer cells to cisplatin. In the present study, we found that the chemotherapy-sensitive ovarian tumor sections showed strong staining for heterochromatin protein 1-γ (HP1-γ), but weak staining for GRP78. Cisplatin-sensitive A2780 cells with low expression of GRP78 tended to undergo senescence easily when compared with the cisplatin-resistant C13K cells following a dose-gradient cisplatin exposure. Forced overexpression of GRP78 protected the cisplatin-sensitive A2780 cells from cisplatin-induced senescence through P53 and CDC2. Knockdown of GRP78 rescued the senescence sensitivity of cisplatin-resistant C13K cells to cisplatin through P21 and CDC2. Twisting of Ca2+ release from ER stores by GRP78 was established to be associated with the sensitivity of cisplatin-induced senescence in ovarian cancer cell lines. In conclusion, GRP78 may have anti-senescence effects on ovarian cancer cells involving multiple mechanisms. Intervention against GRP78 may reduce cisplatin resistance in ovarian cancer.

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1	Selvakumaran M, Pisarcik DA, Bao R, Yeung AT and Hamilton TC: Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res. 63:11–16. 2003.PubMed/NCBI
2	Yang X, Xing H, Gao Q, Chen G, Lu Y, Wang S and Ma D: Regulation of HtrA2/Omi by X-linked inhibitor of apoptosis protein in chemoresistance in human ovarian cancer cells. Gynecol Oncol. 97:413–421. 2005. View Article : Google Scholar : PubMed/NCBI
3	Lee S, Choi EJ, Jin C and Kim DH: Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol. 97:26–34. 2005.PubMed/NCBI
4	Gifford G, Paul J, Vasey PA, Kaye SB and Brown R: The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin Cancer Res. 10:4420–4426. 2004.
5	Williams J, Lucas PC, Griffith KA, et al: Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease. Gynecol Oncol. 96:287–295. 2005. View Article : Google Scholar : PubMed/NCBI
6	Roninson IB: Tumor cell senescence in cancer treatment. Cancer Res. 63:2705–2715. 2003.PubMed/NCBI
7	Elmore LW, Xu Di, Dumur C, Holt SE and Gewirtz DA: Evasion of a single-step, chemotherapy-induced senescence in breast cancer cells: implications for treatment response. Clin Cancer Res. 11:2637–2643. 2005. View Article : Google Scholar : PubMed/NCBI
8	Lee BY, Han JA, Im JS, et al: Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell. 5:187–195. 2006.
9	Bartkova J, Rezaei N, Liontos M, et al: Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 444:633–637. 2006. View Article : Google Scholar : PubMed/NCBI
10	te Poele RH, Okorokov AL, Jardine L, Cummings J and Joel SP: DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 62:1876–1883. 2002.PubMed/NCBI
11	Schmitt CA, Fridman JS, Yang M, et al: A senescence program controlled by p53 and p16^INK4a contributes to the outcome of cancer therapy. Cell. 109:335–346. 2002. View Article : Google Scholar : PubMed/NCBI
12	Roninson IB: Tumour senescence as a determinant of drug response in vivo. Drug Resist Updat. 5:204–208. 2002. View Article : Google Scholar : PubMed/NCBI
13	Fang K, Chiu CC, Li CH, Chang YT and Hwang HT: Cisplatin-induced senescence and growth inhibition in human non-small cell lung cancer cells with ectopic transfer of p16^INK4a. Oncol Res. 16:479–488. 2007. View Article : Google Scholar : PubMed/NCBI
14	Lee AS: The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci. 26:504–510. 2001. View Article : Google Scholar : PubMed/NCBI
15	Ranganathan AC, Zhang L, Adam AP and Aguirre-Ghiso JA: Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res. 66:1702–1711. 2006. View Article : Google Scholar
16	Fu Y, Li J and Lee AS: GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen-starvation induced apoptosis. Cancer Res. 67:3734–3740. 2007. View Article : Google Scholar
17	Reddy RK, Mao C, Baumeister P, Austin RC, Kaufman RJ and Lee AS: Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem. 278:20915–20924. 2003. View Article : Google Scholar : PubMed/NCBI
18	Ermakova SP, Kang BS, Choi BY, et al: (−)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78. Cancer Res. 66:9260–9269. 2006.
19	Davidson DJ, Haskell C, Majest S, et al: Kringle 5 of human plasminogen induces apoptosis of endothelial and tumour cells through surface-expressed glucose-regulated protein 78. Cancer Res. 65:4663–4672. 2005. View Article : Google Scholar
20	Mandic A, Hansson J, Linder S and Shoshan MC: Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem. 278:9100–9106. 2003. View Article : Google Scholar : PubMed/NCBI
21	Lee HK, Xiang CL, Cazacu S, et al: GRP78 is overexpressed in glioblastomas and regulates glioma cell growth and apoptosis. Neuro Oncol. 10:236–243. 2008. View Article : Google Scholar : PubMed/NCBI
22	Jiang CC, Mao ZG, Avery-Kiejda K, Wade M, Hersey P and Zhang XD: Glucose-regulated protein 78 antagonizes cisplatin and adriamycin in human melanoma cells. Carcinogenesis. 30:197–204. 2009. View Article : Google Scholar : PubMed/NCBI
23	Zu K, Bihani T, Lin A, Park YM, Mori K and Ip C: Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. Oncogene. 25:546–554. 2006.PubMed/NCBI
24	Tate S, Hirai Y, Takeshima N and Hasumi K: CA125 regression during neoadjuvant chemotherapy as an independent prognostic factor for survival in patients with advanced ovarian serous adenocarcinoma. Gynecol Oncol. 96:143–149. 2005. View Article : Google Scholar : PubMed/NCBI
25	Wang W, Wang S, Song X, et al: The relationship between c-FLIP expression and human papillomavirus E2 gene disruption in cervical carcinogenesis. Gynecol Oncol. 105:571–577. 2007. View Article : Google Scholar : PubMed/NCBI
26	Hawkins LK, Johnson L, Bauzon M, et al: Gene delivery from the E3 region of replicating human adenovirus: evaluation of the 6.7 K/gp19 K region. Gene Ther. 8:1123–1131. 2001. View Article : Google Scholar : PubMed/NCBI
27	Fernandez PM, Tabbara SO, Jacobs LK, et al: Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat. 59:15–26. 2000. View Article : Google Scholar : PubMed/NCBI
28	Koomägi R, Mattern J and Volm M: Glucose-related protein (GRP78) and its relationship to the drug-resistance proteins P170, GST-pi, LRP56 and angiogenesis in non-small cell lung carcinomas. Anticancer Res. 19:4333–4336. 1999.PubMed/NCBI
29	Taylor DD, Gercel-Taylor C and Parker LP: Patient-derived tumor-reactive antibodies as diagnostic markers for ovarian cancer. Gynecol Oncol. 115:112–120. 2009. View Article : Google Scholar : PubMed/NCBI
30	Arap MA, Lahdenranta J, Mintz PJ, et al: Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell. 6:275–284. 2004. View Article : Google Scholar : PubMed/NCBI
31	Zhou H, Zhang Y, Fu Y, Chan L and Lee AS: Novel mechanism of anti-apoptotic function of 78-kDa glucose-regulated protein (GRP78): endocrine resistance factor in breast cancer, through release of B-cell lymphoma 2 (BCL-2) from BCL-2-interacting killer (BIK). J Biol Chem. 286:25687–25696. 2011. View Article : Google Scholar
32	Petroulakis E, Parsyan A, Dowling RJ, et al: p53-dependent translational control of senescence and transformation via 4E-BPs. Cancer Cell. 16:439–446. 2009. View Article : Google Scholar : PubMed/NCBI
33	Gannon HS, Donehower LA, Lyle S and Jones SN: Mdm2-p53 signaling regulates epidermal stem cell senescence and premature aging phenotypes in mouse skin. Dev Biol. 353:1–9. 2011. View Article : Google Scholar : PubMed/NCBI
34	Vaziri H, West MD, Allsopp RC, et al: ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase. EMBO J. 16:6018–6033. 1997. View Article : Google Scholar : PubMed/NCBI
35	Abbas T and Dutta A: p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 9:400–414. 2009. View Article : Google Scholar : PubMed/NCBI
36	Shen H and Maki CG: Persistent p21 expression after Nutlin-3a removal is associated with senescence-like arrest in 4N cells. J Biol Chem. 285:23105–23114. 2010. View Article : Google Scholar : PubMed/NCBI
37	Roberson RS, Kussick SJ, Vallieres E, Chen SY and Wu DY: Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res. 65:2795–2803. 2005. View Article : Google Scholar : PubMed/NCBI
38	Giorgi C, Ito K, Lin HK, et al: PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science. 330:1247–1251. 2010. View Article : Google Scholar : PubMed/NCBI