THE ROLE OF SIRTUIN 3 IN OVARIAN CANCER METASTASIS
Open Access
- Author:
- Jones, Victoria M
- Graduate Program:
- Biomedical Sciences
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- July 28, 2016
- Committee Members:
- Nadine Hempel, Thesis Advisor/Co-Advisor
Kent Vrana, Committee Member
Lisa M Shantz, Committee Member
Rebecca Phaeton, Committee Member - Keywords:
- SIRT3
Sirtuin 3
Ovarian Cancer
SOD2
Spheroids
Mitochondria - Abstract:
- Epithelial ovarian cancer (EOC) is highly metastatic with late-onset symptoms, making it the leading cause of death in women with gynecologic malignancies. The proposed mechanism of metastasis involves aggressive, free-floating spheroid-like cellular aggregates that shed from the primary tumor, survive for some time in anchorage independence and eventually invade the omentum of the peritoneal cavity and nearby organs. Preliminary data revealed an upregulation of the antioxidant superoxide dismutase (SOD2) in ovarian cancer spheroids and confirmed its recently emerging, dichotomous role as a tumor promoter. We hypothesized that sirtuin 3 (SIRT3), a key regulator of SOD2, would similarly be increased in spheroids and help to promote ovarian cancer metastasis. While we observed the SIRT3 protein increase in ovarian cancer spheroids, we unexpectedly saw – upon generating SIRT3 shRNA-mediated knockdown cells – an increase in metastatic functions such as migration and proliferation. These data point to a tumor suppressive function of SIRT3 in ovarian cancer, as previously established in breast cancer. Interestingly, bioenergetics analysis characterized SIRT3 knockdown cells as having increased rates of glycolysis and glucose-dependent mitochondrial respiration. Moreover, they displayed a dependency on glucose for cell survival, while those cells with SIRT3 expression were able to survive in glucose-depleted conditions. These results may hint at clues as to why ovarian cancer spheroids increase expression of SIRT3 during the anchorage-independent stage of metastasis in the ascites fluid-containing peritoneal cavity. Efforts are underway to establish if a transient increase in SIRT3 during this anchorage-independent spheroid stage enhances cellular metabolic flexibility to rely on alternate fuel sources in situations of glucose deprivation, as may be the case in the ascites fluid.