Ovarian cancer is the fifth leading cause of cancer-related death in the United States. The standard first line chemotherapy to treat this deadly disease includes platinum (cisplatin/carboplatin)-based treatment, but the development of drug resistance presents a significant clinical problem that needs to be addressed. Our current study identifies a novel mechanism of cisplatin resistance involving autophagy-related gene (Atg) 5. Atg5 is a member of the Atg family that plays an important role in regulating autophagy, a process essential for the quality control of cellular components under various stress conditions. Previous studies showed that the inhibition of autophagy sensitizes cancer cells to chemotherapy. Our own study showed that the blockade of autophagy induction promotes cisplatin sensitivity in human ovarian cancer cells, but strategies for targeting autophagy in cancer therapies in general are not well developed. We find that Atg5 is overexpressed in human ovarian tumors, and that its overexpression inhibits cisplatin-induced apoptosis in ovarian cancer cells. We also find that Atg5 overexpression is correlated with the poor overall survival in ovarian cancer patients treated with platinum-based chemotherapy. Additionally, we find that Atg5 is phosphorylated but the effects of its phosphorylation on Atg5-mediated autophagy and cisplatin resistance remain to be determined. Based on these novel observations, we hypothesize that elevated Atg5 expression confers growth advantage of ovarian cancer cells by promoting cell survival and drug resistance. The objectives of this project are to define the role of Atg5 in cisplatin resistance and the impact of Atg5 phosphorylation on cisplatin resistance. These objectives will be achieved by the following two Specific Aims: 1) Define the role of Atg5 in cisplatin resistance both in vitro and in vivo using ovarian cancer mouse models; and 2) Determine the regulation of Atg5 phosphorylation and its impact on cisplatin resistance. Successful results from this study could lead to the development of novel therapeutic strategies for treating ovarian cancer patients.
Platinum (cisplatin/carboplatin)-based treatment is the first line chemotherapy for patients with ovarian cancer, but the development of chemoresistance results in the treatment failure. This application will define Atg5 as a novel therapeutic target that can be developed for improving platinum-based chemotherapies for ovarian cancer. The proposed research has relevance to public health and is highly translational with potential clinical impact.
