Abstract 4135: Cisplatin resistance promotes cell motility and migration through EGF receptor-mediated Erk and Stat3 pathways in human ovarian cancer cells

Abstract

Abstract Ovarian cancer causes the highest gynecologic neoplasm-related deaths in the United States. A common feature of ovarian cancer is the wide dissemination of the disease in the peritoneum at the time of presentation by the patient, which poses an added challenge to therapy in terms of the ability to completely eliminate the disease tissue. Moreover, disease recurrence is common and frequently associated with drug resistance. Cisplatin has been the most active drug for the treatment of ovarian cancer for the last decades. 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. Here, we developed Cisplatin resistance in vitro to address the molecular and biological mechanisms that may be presented by the recurrent disease. The cell characteristic changes and the molecular basis of resistance to Cisplatin were investigated using the Cisplatin-resistant human ovarian cancer cell lines, A2780S/CP1, A2780S/CP3 and A2780S/CP5, which were derived from the parental, Cisplatin-sensitive line, A2780S and are resistant to 1, 3 and 5 μM Cisplatin, respectively. Cell morphology under bright-field microscope showed marked changes in the Cisplatin-resistant cells compared to that of the parental cells. Notably, wound healing and migration assays showed significantly enhanced cell motility and migration properties in Cisplatin-resistant clones. Furthermore, resistance to Cisplatin enhanced the ability of cells to form colonies. Molecular mechanistic analysis indicated that Cisplatin resistance in A2780S/CP3 and A2780S/CP5 cells dramatically activated the EGF receptor (EGFR)-Erk1/2MAPK and EGFR-Stat3 pathways, and upregulated the expression of cellular survival genes such as Bcl-xL and Survivin. Accordingly, treatment of the Cisplatin-resistant A2780S/CP3 and A2780S/CP5 lines with the EGFR inhibitor, Iressa or the Stat3 inhibitor, S3I-201 significantly attenuated colony survival and cell migration. Moreover, resistance to Cisplatin led to the upregulation of the expression of F-actin and cortactin, and promoted the assembly of F-actin at the front of lamellipodia in A2780S/CP3 and A2780S/CP5 lines. These results 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 cell survival, 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 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4135.