Abstract 1956: Enhanced colony-forming ability, and motility and migratory properties of Cisplatin-resistant ovarian cancer cells

Abstract

Abstract Ovarian cancer causes the highest gynecologic neoplasm-related deaths in the United States. Although the majority of ovarian cancer patients respond to Cisplatin therapy, most develop recurrent and resistant disease, raising the need to understand the molecular mechanisms that support the resistant phenotype and to identify novel effective therapeutic and chemo-sensitizing modalities. In this study, we developed Cisplatin resistance in vitro to address the molecular and biological mechanisms that may be presented by the recurrent disease. The resistant lines, A2780S/CP3 and A2780S/CP5, which were derived from the Cisplatin-sensitive line, A2780S and are resistant to 3 and 5 μM Cisplatin, respectively, showed marked changes in morphology, compared to the parental cells. Notably, both resistant lines showed enhanced colony-forming ability and significantly enhanced cell motility and migratory properties. Molecular mechanistic analysis indicated the Cisplatin resistance was associated with hyperactive epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinase (Erk)1/2MAPK and EGFR-Signal Transducer and Activator of Transcription (Stat)3 pathways, the overexpression of Survivin and vascular endothelial growth factor receptor (VEGF), and F-actin and Cortactin, with F-actin localization that is predominantly at the cellular extensions. Treatment of the Cisplatin-resistant A2780S/CP5 line with the EGFR inhibitor, Iressa or the Stat3 inhibitor, S3I-201 inhibited the colony-forming ability of these cells, without suppressing their viability, suggesting EGFR-Erk1/2 and EGFR-Stat3 activation are required for the proliferation of the resistant cells. Furthermore, inhibition of EGFR or Stat3 activation significantly suppresses the migration of A2780S/CP3 cells, while the motility of both A2780S/CP3 and A2780S/CP5 lines are sensitive to EGFR inhibition. These results together suggest that Cisplatin resistance in ovarian cancer is mediated in part through the activation of the EGF receptor-mediated Erk and Stat3 pathways that promote increased cell proliferation, motility and migration. These findings raise the possibility that EGFR or Stat3 inhibitors combined with Cisplatin may be an effective therapeutic approach for Cisplatin-resistant ovarian cancer. 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 1956. doi:10.1158/1538-7445.AM2011-1956