Increased expression and activity of Sod2 promotes transcoelomic metastasis in ovarian cancer

Ovarian cancer is the leading cause of death from gynecologic malignancy due to asymptomatic progression of the disease to advanced stages. Patients with widespread metastases are characterized by a large volume of ascites in the peritoneal cavity within which floating cancer cell populations are found in malignant cases. Metastasis of ovarian cancer occurs when cancer cells escape the primary tumor and adapt to survive under stress conditions associated with anchorage independence in the ascites. We demonstrate that ovarian cancer cells overcome matrix detachment-induced oxidative stress by upregulating expression and activity of the mitochondrial antioxidant enzyme Manganese Superoxide Dismutase 2 (Sod2), and demonstrate that increased expression of Sod2 in anchorage independence is necessary for survival of ovarian cancer cell in vitro and for successful omental metastasis in vivo. Our data reveal a multi-modal regulation of Sod2 in anchorage independence, that includes transcriptional, translational and post-translational regulation at different stages following matrix detachment. In early anchorage independence, a rapid increase in Sod2 protein translation is observed within 30 minutes after cell detachment, without change in mRNA expression. Concomitantly, Sod2 activity is rapidly increased following matrix detachment in a Sirtuin-3 (SIRT3)-dependent manner. We demonstrate that SIRT3, a mitochondrial NAD+ deacetylase, which activates Sod2 by deacetylating key lysine residues including K68, is also necessary for anchorage independent survival and metastasis in vivo. This early post-transcriptional/post-translational regulation of Sod2 is followed by increased mRNA transcription and protein expression of Sod2 within 24 hours of anchorage independence. Concomitantly, we observe increased expression of the stress-response transcription factor Nrf2, a master regulator of antioxidant genes, including Sod2. Collectively, our data suggest that ovarian cancer cells exhibit a multi-modal regulatory system to ensure rapid and sustained expression and activity of Sod2 in response to anchorage independence, which provides protection from mitochondrial oxidative stress associated with transcoelomic metastasis.