Regulation of Ovarian Cancer Cell Metabolism by SIRT5
Abstract
Rationale: In recent years, many studies have defined alterations in cellular metabolism that occur in the context of cancer. Cancer cells undergo "metabolic reprogramming" to allow rapid synthesis of biomolecules and promote tumor growth. Reversal of these changes has been shown to induce cell death in cancer cells, while sparing normal cell types. Little is currently known about metabolic reprogramming in ovarian carcinoma specifically. Characterization of altered metabolism in ovarian carcinoma will likely provide novel therapeutic targets for disease treatment. Our laboratory studies the sirtuin proteins, a family of enzymes that control metabolism in many cell and tissue types. We have found that one of these proteins, SIRT5, regulates metabolism in ways highly reminiscent of cancer cell metabolic reprogramming. Thirty percent of ovarian carcinomas have additional copies of the SIRT5 gene, and the SIRT5 protein is present at very high levels in the great majority of ovarian carcinomas. Altogether, these observations suggest that SIRT5 may represent an attractive new therapeutic target in ovarian carcinoma. Importantly, deletion of the Sirt5 gene in mice causes only very mild defects, suggesting that drugs that inhibit SIRT5 would be clinically well tolerated by ovarian carcinoma patients. Drugs that selectively inhibit other sirtuin enzymes have already been identified, suggesting that SIRT5 inhibitors could be developed in a straightforward manner. Indeed, we are currently collaborating with a chemist at the University of Michigan to develop such inhibitors. Objective: In this application, we propose to directly test the role of SIRT5 in ovarian carcinomas. We will reduce SIRT5 levels in a panel of ovarian carcinoma cells and test whether this impairs growth and sensitizes the cells to genotoxic chemotherapy. As part of this analysis, we will dissect the effects of SIRT5 on ovarian carcinoma cellular metabolism using a variety of cutting-edge approaches. We will also delete the Sirt5 gene in a mouse strain prone to ovarian carcinoma to determine whether this reduces cancer development and impacts tumor metabolism. Overall, these studies will potentially establish SIRT5 as a novel target in ovarian carcinoma. More generally, they will provide new insights into metabolic reprogramming in ovarian carcinoma, perhaps revealing new therapeutic opportunities in this deadly disease. Relevance to the Ovarian Cancer Research Program (OCRP) Mission: One of the OCRP s stated priorities is to "understand ... pathogenesis/progression of all types of ovarian cancer." Our published and unpublished work indicates that SIRT5 is present at high levels in most ovarian carcinomas, where it appears to play a role in promoting cancer-type metabolism. The experiments in this application will evaluate whether SIRT5 depletion will attenuate the malignant properties of ovarian carcinoma cells, using both human tumor cell lines and mouse models. If successful, these experiments may ultimately lead to therapeutic targeting of SIRT5 as a treatment for ovarian cancer. Thus, the studies laid out in this application fit very well within the OCRP s mission. Impact: Ovarian carcinoma is the most lethal gynecologic malignancy and will claim over 14,000 lives in the United States this year alone. Despite modest therapeutic advances, the prognosis for ovarian carcinoma that has spread beyond the ovary remains poor, with a 5-year survival rate of less than 30%. These grim statistics highlight the urgent need for development of novel approaches to treat ovarian carcinoma. Little information is currently available regarding the incidence of ovarian carcinoma in military Servicewomen specifically, or in military beneficiaries more broadly. Although ovarian carcinoma tends to occur in older women, a recent study found that the average age of ovarian carcinoma in U.S. Air Force active duty women was 35, and approximated the i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510062
Entities
People
- David B. Lombard
Organizations
- United States Army
- University of Michigan