Abstract 4971: Identification of statins as a potential treatment for ovarian cancer

Abstract

Abstract Late-stage diagnoses make ovarian cancer extremely hard to treat. This leads to ovarian cancer accounting for 5% of female cancer deaths and 2.5% of female cancer incidence. Since there are few options for early detection of ovarian cancer, targeted therapies could lead to better outcomes. One target that has been implicated in ovarian cancer, is the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 function is associated with tumor growth, metastasis, drug resistance, angiogenesis, and resistance to apoptosis. These many STAT3 controlled, cancer-associated cellular functions, make it an ideal and versatile target for cancer therapy. Using the Broad institute’s online C.L.U.E. tool and a STAT3 gene signature, we identified statin drugs as potential inhibitors of STAT3 activity. To assess the ability of statins to inhibit STAT3, we treated ovarian cancer spheroids with statins and analyzed STAT3 activity. We have found that statins do not induce a change in the phosphorylation of STAT3 on either tyrosine 705 or serine 727 residues, the two major sites of phosphorylation on STAT3. However, there are other poorly understood post-translational modifications of STAT3, that have previously shown effects on STAT3 function, that may be involved. Importantly, we have observed that statin treatment reduces the viability of Ovcar8 and Heya8 ovarian cancer cell spheroids. We also found that statin treatment induced apoptosis of ovarian spheroids by measuring Annexin V staining. A major problem for ovarian cancer patients is metastasis. Our preliminary evidence suggests that statins reduce the ability of ovarian cancer spheroids to clear a mesothelial monolayer of cells, an early step in ovarian cancer metastasis. There are several membrane-associated signaling proteins, including RAF and RAS, that affect STAT3 activity. Both Ovcar8 and Heya8 spheroids showed a decrease in cell viability with statin treatment, which is partially rescued by geranylgeranyl pyrophosphate (GGPP), a downstream metabolite in the mevalonate pathway. The partial recovery by GGPP indicates a mechanism involving the prenylation of membrane associated proteins. This data shows statins may provide effective treatments for ovarian cancer and defining the mechanisms behind the effects of statins may lead to better therapies and outcomes for ovarian cancer patients Citation Format: Brendan M. Reilly, Sarah J. Miseirvitch, Sarah R. Walker. Identification of statins as a potential treatment for ovarian cancer . [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4971.