Abstract 5048: TAp73a enhances the cellular chemosensitivity to cisplatin in ovarian cancer cells

Abstract

Abstract Ovarian cancer is the most lethal gynecological malignancy. Most ovarian cancer patients relapse and subsequently die due to the development of resistance to chemotherapy. Strategies for overcoming resistance to chemotherapy and improving prognosis of ovarian cancer patients are very critical. P73, one member of the tumor suppressor p53 family, shares highly structural and functional similarity to p53. Established evidence showed that p73 mediated cellular sensitivity to chemotherapeutic agents in some human tumor cells. However, the role of p73 in the regulation of cellular response to DNA damaging agents in ovarian cancer is still poorly understood, and the function of the transcriptionally active isoform TAp73 as a tumor suppressor is still controversial. The aim of the present study was to examine the effect of TAp73a on cellular response to commonly used chemotherapeutic agent cisplatin in ovarian cancer cells. We established TAp73a overexpressed stable clones in two ovarian cancer cell lines: OVCA433 (wild-type p53) and SKOV3 (null p53). We found that TAp73a enhanced chemosensitivity of ovarian cancer cells to cisplatin by inhibiting cell growth and inducing cell cycle arrest and apoptosis in wild-type p53 OVCA433 cells. Additionally, TAp73a up-regulated the p53 expression and its downstream genes: PUMA, NOXA, p53AIP1, and down-regulated the phosphorylation of Akt as assessed by western blotting. The accumulation of p53 protein induced by TAp73a was found at the post-transcriptional level. Co-immunoprecipitation assay demonstrated that TAp73a directly bound to p53 protein, suggesting that such interaction might block the degradation of p53 protein in OVCA433 cells. In p53-null SKOV3 cells, the increase of chemosensitivity induced by TAp73a was also observed, indicating that TAp73a also functioned independent of p53 by up-regulating the cell cycle inhibitor p21 expression. In conclusion, these results suggested that TAp73a might play an important role in the enhancement of cellular sensitivity to chemotherapeutic drug cisplatin in ovarian cancer cells through p53 dependent and independent pathways. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 5048.