Abstract 1708: Induction of GDF15 by cisplatin triggers apoptotic cell death in ovarian cancer cells

Abstract

Abstract Ovarian cancer is the fifth most common cause of death among women. The overall five year survival is 45.6% as a result of late diagnosis when treatment is mostly ineffective. Current treatment consists of complete resection followed by a combination of a taxane and a platinum -based chemotherapy regardless of the subtype. After standard treatment, 70% of patients will develop chemoresistance, creating a major challenge in the treatment of this type of cancer. Therefore, there is great interest in understanding the mechanisms by which tumors develop resistance. From the microarray data of a high grade serous ovarian cancer cell line (A2780) treated with varying concentrations of cisplatin and at varying time points, we identified four genes (CDKN1A, FDXR, TP53I3 and GDF15) which were significantly up-regulated by cisplatin in a time and dose dependent manner. The time and dose dependent upregulation of these genes were further validated by real-time RT-PCR and Western blot analysis in A2780 and two other ovarian cancer cell lines. We further tested whether GDF15 expression correlated with cisplatin response. RNA and protein from 6 different cell lines with different IC50 to cisplatin revealed a positive correlation between GDF15 induction and sensitivity to cisplatin. To further investigate the role GDF15 plays in the chemoresponse of ovarian cancer cell, we knocked down the expression of GDF15 by shRNA. Ovarian cancer cells with GDF15 knockdown showed a decrease in PARP cleavage, suggesting a pro-apoptotic role for GDF15. Thus, our results suggest that induction of GDF15 by cisplatin is one of the mechanisms that triggers apoptotic cell death in ovarian cancer cells. On the other hand, we were not able to detect an induction of GDF15 by cisplatin in a cisplatin resistant cell line A2780cp20. Thus, the lost of GDF15 induction could be one of the mechanisms of developing chemoresistance. Future studies to decipher the mechanism by which cisplatin induces GDF15 expression have the potential of identifying new targets that could circumvent chemoresistance to cisplatin. 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 1708. doi:10.1158/1538-7445.AM2011-1708