Abstract
Abstract Ovarian Cancer causes the highest number of gynecologic neoplasm related deaths in the United States. The disease and its progression to drug resistance remain poorly understood. While the aberrant activation of the Signal Transducer and Activator of Transcription (Stat) 3 protein is prevalent in ovarian cancer and is detected in chemotherapy resistance, its exact role in the development and maintenance of the drug resistance phenotype remains poorly understood. We sought to investigate the molecular mechanisms by which constitutive Stat3 activity may support Cisplatin resistance in ovarian cancer. Compared to the sensitive A2780S ovarian cancer line, which does not harbor aberrant Stat3 activity, the SKOV3 line harboring constitutively-active Stat3 was partially sensitive to Cisplatin and showed evidence of moderate apoptosis in response to Cisplatin treatment. Compared to the sensitive A2780S cells, the partly-resistant, SKOV3 cells over-express c-Myc, Survivin, and Bcl-xL, and the XIAP anti-apoptotic factor, as well as VEGF pro-angiogenic factor and the matrix metalloproteinases, MMP-2 and MMP-9. The inhibition of constitutively-active Stat3 in SKOV3 cells by the small-molecule inhibitor, S3I-201 suppressed the expression of the anti-apoptotic and the pro-angiogenic factors, and induced moderate degree of apoptosis. Significantly, treatment with S3I-201 enhanced the sensitivity of SKOV3 cells to Cisplatin. Furthermore, the combined treatment of SKOV3 cells with Cisplatin and S3I-201 strongly inhibited colony formation and cell migration in vitro. Our study together identifies potential mechanisms by which aberrant Stat3 activity might support Cisplatin resistance in ovarian cancer, raising the potential that the combination therapy with Stat3 inhibitors would be effective therapeutic and chemo-sensitizing modalities for ovarian cancer and the recurrent disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1532. doi:10.1158/1538-7445.AM2011-1532
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