Abstract MIP-059: MITOCHONDRIAL DYNAMICS AND DYSFUNCTION IN OVARIAN CANCER

Abstract

Abstract Altered mitochondrial function remains a key feature of many tumor cells and drives pathways such gene expression, metabolic and stress responses, cell cycle progression and resistance to apoptosis. Many chemotherapeutics activate programmed cell death and it is thought that mitochondrial dysfunction may be one mechanism by which cancer cells evade killing by these compounds. Screening the metabolic profiles of ovarian cancer cell lines and patient ascites-derived tumor cells reveals that ovarian cancers fall into unique bioenergetic subgroups. For example, Ovarian Clear Cell Carcinomas (OCCC) display high oxygen consumption rate and glycolytic flux compared to the more common high grade serous adenocarcinoma (HGSA) subtype. In addition, we show that a portion of HGSAs have severe mitochondrial dysfunction, that is marked by a decrease in mitochondrial respiration, a lack of response to the uncoupler FCCP and a concomitant reliance on alternate metabolic pathways. Moreover, this is accompanied by enhanced chemoresistance to Cisplatin and Taxol. The cause of mitochondrial dysfunction has been attributed to a number of factors, including deregulation in mitochondrial fission/fusion dynamics. Moreover, fission is an integral component of apoptotic and authophagy pathways. Interestingly, the observed HGSA mitochondrial dysfunction correlates with aberrant fusion/fission dynamics and expression of a low molecular weight variant of the mitochondrial fission protein Drp1. The potential significance of Drp1 in ovarian cancer etiology is highlighted by TCGA data, where more than 15% of HGSA samples display significant increases in Drp1 mRNA levels, and associated amplification of the Drp1 gene DNM1L. Whether this represents the shorter, potentially dominant-negative Drp1 variant identified in our work is currently under active investigation. Our data suggest that compromised mitochondrial function and fission/fusion dynamics may be a hallmark of a previously unidentified subgroup of highly chemoresistant EOCs and that this is associated with aberrant expression of the fission protein Drp1. Studies are underway to identify the molecular identity and regulation of short Drp1, and the mechanistic links to alterations in fission, metabolic switching and chemoresistance. Citation Format: Dong-Hui Shin, Usawadee Dier, Patrick F. Timmins, Joshua Kesterson, Rebecca Phaeton and Nadine Hempel. MITOCHONDRIAL DYNAMICS AND DYSFUNCTION IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-059.