Abstract
We present evidence that the cisplatin-resistant human ovarian cancer lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3) and A2780S/CP5 (S/CP5), derived by subjecting the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments followed by recovery and are resistant to 1, 3 and 5 μM cisplatin, respectively, have increased colony-forming ability and altered morphology that is consistent with enhanced motility, migration and invasiveness in vitro. The malignant phenotype progresses with increasing resistance and is associated with hyperactive epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (Erk)1/2 and janus kinases (Jaks), aberrant signal transducer and activator of transcription (Stat) 3 activation promoted by EGFR and Jaks, and epithelial-mesenchymal transition (EMT) in vitro. Survivin and FLIP anti-apoptotic factors, vascular endothelial growth factor (VEGF) and matrix metalloproteinase activities are also elevated in the resistant cells. Accordingly, the ectopic expression of constitutively-active Stat3C in the sensitive A2780S cells diminished cisplatin sensitivity. The inhibition of EGFR or Stat3 activity repressed Survivin, VEGF and Vimentin expression and the colony-forming potential, viability, motility and migration of the resistant cells, and sensitized them to cisplatin. Analysis of human ovarian cancer patients’ tumor tissues shows aberrantly-active EGFR and Stat3 that in certain cases correlate with Vimentin over-expression. Intra-peritoneal mouse xenograft studies revealed, compared with the sensitive A2780S line that had low tumor incidence restricted to the ovary, a high tumor incidence for the resistant S/CP3 and S/CP5 lines that formed tumor nodules at several locations on the small intestine and colon, and which responded poorly to cisplatin, but were sensitive to concurrent treatment with cisplatin and EGFR or Stat3 inhibitor. Hyperactive EGFR signaling through Stat3 and the Jak-Stat3 activity together promote ovarian cancer progression to cisplatin resistance and therefore represent targets for preventing the development of cisplatin resistance and the recurrent disease during cisplatin therapy in ovarian cancer.
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Abbreviations
- EGFR:
-
epidermal growth factor receptor
- EMT:
-
epithelial-mesenchymal transition
- Jak:
-
Janus kinase
- MAPK:
-
mitogen-activated protein kinase
- MEK, MAP:
-
kinase kinase
- PD:
-
PD98059
- S3I:
-
S3I-201
- STAT:
-
signal transducer and activator of transcription
- VEGF:
-
vascular endothelial growth factor;
- ZD:
-
ZD1839 (Iressa)
References
Ahmed N, Thompson EW, Quinn MA . (2007). Epithelial-mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas: an exception to the norm. J Cell Physiol 213: 581–588.
Aoki Y, Feldman GM, Tosato G . (2003). Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 101: 1535–1542.
Arany I, Megyesi JK, Kaneto H, Price PM, Safirstein RL . (2004). Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells. Am J Physiol Renal Physiol 287: F543–F549.
Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL et al. (2009). Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 69: 5820–5828.
Avizienyte E, Frame MC . (2005). Src and FAK signalling controls adhesion fate and the epithelial-to-mesenchymal transition. Curr Opin Cell Biol 17: 542–547.
Bhattacharya S, Ray RM, Johnson LR . (2005). STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells. Biochem J 392: 335–344.
Blume-Jensen P, Hunter T . (2001). Oncogenic kinase signalling. Nature 411: 355–365.
Bowden ET, Barth M, Thomas D, Glazer RI, Mueller SC . (1999). An invasion-related complex of cortactin, paxillin and PKCm associates with invadopodia at sites of extracellular matrix degradation. Oncogene 18: 4440–4449.
Bowman T, Garcia R, Turkson J, Jove R . (2000). STATs in oncogenesis. Oncogene 19: 2474–2488.
Brabec V, Kasparkova J . (2005). Modifications of DNA by platinum complexes. Relation to resistance of tumors to platinum antitumor drugs. Drug Resist Updat 8: 131–146.
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C et al. (1999). Stat3 as an Oncogene. Cell 98: 295–303.
Burke WM, Jin X, Lin HJ, Huang M, Liu R, Reynolds RK et al. (2001). Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene 20: 7925–7934.
Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R et al. (1999). Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10: 105–115.
Chan JK, Pham H, You XJ, Cloven NG, Burger RA, Rose GS et al. (2005). Suppression of ovarian cancer cell tumorigenicity and evasion of Cisplatin resistance using a truncated epidermal growth factor receptor in a rat model. Cancer Res 65: 3243–3248.
Cui W, Yazlovitskaya EM, Mayo MS, Pelling JC, Persons DL . (2000). Cisplatin-induced response of c-jun N-terminal kinase 1 and extracellular signal—regulated protein kinases 1 and 2 in a series of cisplatin-resistant ovarian carcinoma cell lines. Mol Carcinog 29: 219–228.
Dancey JE, Freidlin B . (2003). Targeting epidermal growth factor receptor—are we missing the mark? Lancet 362: 62–64.
Darnell JE . (2005). Validating Stat3 in cancer therapy. Nat Med 11: 595–596.
Desai B, Ma T, Chellaiah MA . (2008). Invadopodia and matrix degradation, a new property of prostate cancer cells during migration and invasion. J Biol Chem 283: 13856–13866.
Duan Z, Foster R, Bell DA, Mahoney J, Wolak K, Vaidya A et al. (2006). Signal Transducers and Activators of Transcription 3Pathway Activation in Drug-Resistant Ovarian Cancer. Cancer Res 12: 5056–5063.
Epling-Burnette PK, Lui JH, Catlette-Falcone R, Turkson J, Oshiro M, Kothapalli R et al. (2001). Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 107: 351–362.
Fajac A, Da Silva J, Ahomadegbe JC, Rateau JG, Bernaudin JF, G R et al. (1996). Cisplatin-induced apoptosis and p53 gene status in a cisplatin-resistant human ovarian carcinoma cell line. Int J Cancer 68: 67–74.
Gallagher WM, Cairney M, Schott B, Roninson IB, Brown R . (1997). Identification of p53 genetic suppressor elements which confer resistance to cisplatin. Oncogene 14: 185–193.
Gan Y, Shi C, Inge L, Hibner M, Balducci J, Huang Y . (2010). Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells. Oncogene 29: 4947–4958.
Gonzalez VM, Fuertes MA, Alonso C, Perez JM . (2001). Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol 59: 657–663.
Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M et al. (2006). Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12: 11–19.
Huang M, Page C, Reynolds RK, Lin J . (2000). Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells. Gynecol Oncol 79: 67–73.
Ikuta K, Takemura K, Kihara M, Naito S, Lee E, Shimizu E et al. (2005). Defects in apoptotic signal transduction in cisplatin-resistant non-small cell lung cancer cells. Oncol Rep 13: 1229–1234.
Kassouf W, Dinney CP, Brown G, McConkey DJ, Diehl AJ, Bar-Eli M et al. (2005). Uncoupling between epidermal growth factor receptor and downstream signals defines resistance to the antiproliferative effect of Gefitinib in bladder cancer cells. Cancer Res 65: 10524–10535.
Kelland LR, Sharp SY, O'Neill CF, Raynaud FI, Beale PJ, Judson IR . (1999). Mini-review: discovery and development of platinum complexes designed to circumvent cisplatin resistance. J Inorg Biochem 77: 111–115.
Kim YK, Kim HJ, Kwon CH, Kim JH, Woo JS, Jung JS et al. (2005). Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells. J Appl Toxicol 25: 374–382.
Lee MY, Chou CY, Tang MJ, Shen MR . (2008). Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation. Clin Cancer Res 14: 4743–4750.
Matsuo M, Sakurai H, Koizumi K, Saiki I . (2007). Curcumin inhibits the formation of capillary-like tubes by rat lymphatic endothelial cells. Cancer Lett 251: 288–295.
Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J et al. (2002). Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21: 2000–2008.
Richardson A, Kaye SB . (2005). Drug resistance in ovarian cancer: the emerging importance of gene transcription and spatio-temporal regulation of resistance. Drug Resist Updat 8: 311–321.
Selvendiran K, Bratasz A, Kuppusamy ML, Tazi MF, Rivera BK, Kuppusamy P . (2009). Hypoxia induces chemoresistance in ovarian cancer cells by activation of signal transducer and activator of transcription 3. Int J Cancer 125: 2198–2204.
Selvendiran K, Bratasz A, Tong L, Ignarro LJ, Kuppusamy P . (2008). NCX-4016, a nitro-derivative of aspirin, inhibits EGFR and STAT3 signaling and modulates Bcl-2 proteins in cisplatin-resistant human ovarian cancer cells and xenografts. Cell Cycle 7: 81–88.
Shao H, Cheng HY, Cook RG, Tweardy DJ . (2003). Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res 63: 3923–3930.
Siddiquee K, Glenn M, Gunning P, Katt WP, Zhang S, Schroeck C et al. (2007a). An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects. ACS Chem Biol 2: 787–798.
Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence H et al. (2007b). Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA 104: 7391–7396.
Song H, Sondak VK, Barber DL, Reid TJ, Lin J . (2004). Modulation of Janus kinase 2 by cisplatin in cancer cells. Int J Oncol 24: 1017–1026.
Thiery JP . (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.
Tice DA, Biscardi JS, Nickles AL, Parsons SJ . (1999). Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc Natl Acad Sci USA 96: 1415–1420.
Turkson J . (2004). STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets 8: 409–422.
Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R . (1998). Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Cell Biol 18: 2545–2552.
Villedieu M, Deslandes E, Duval M, Heron JF, Gauduchon P, Poulain L . (2006). Acquisition of chemoresistance following discontinuous exposures to cisplatin is associated in ovarian carcinoma cells with progressive alteration of FAK, ERK and p38 activation in response to treatment. Gynecol Oncol 101: 507–519.
Wang G, Reed E, Li QQ . (2004). Molecular basis of cellular response to cisplatin chemotherapy in non-small cell lung cancer (Review). Oncol Rep 12: 955–965.
Yu H, Jove R . (2004). The STATS of Cancer-New molecular targets come of age. Nat Rev Cancer 4: 97–105.
Zhang X, Yue P, Fletcher S, Zhao W, Gunning PT, Turkson J . (2010). A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes. Biochem Pharmacol 79: 1398–1409.
Zhang Y, Turkson J, Carter-Su C, Smithgall T, Levitzki A, Kraker A et al. (2000). Activation of Stat3 in v-Src Transformed Fibroblasts Requires Cooperation of Jak1 Kinase Activity. J Biol Chem 275: 24935–24944.
Acknowledgements
We thank all colleagues and members of our laboratory for the stimulating discussions and the University of Central Florida Confocal Microscopy and the Transgenic Animal facilities for their assistance. This work was supported by the National Cancer Institute Grants CA106439 and CA128865 (to JT) and the Florida Hospital-UCF-Gala Endowed Program for Oncologic Research Award (JT and RWH) and the State of Florida Bankhead-Coley Cancer Research Program (SBI, RWH and SA).
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Yue, P., Zhang, X., Paladino, D. et al. Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells. Oncogene 31, 2309–2322 (2012). https://doi.org/10.1038/onc.2011.409
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DOI: https://doi.org/10.1038/onc.2011.409
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