Abstract LB125: The role of succinate dehydrogenase in ovarian cancer metabolism

Abstract

Abstract The reprogramming of cellular metabolism is an important hallmark of cancer allowing tumor cells to survive and proliferate. Recent data revealed that subsets of ovarian cancer with invasive and metastatic phenotype are highly metabolically active with increased mitochondrial respiration. To better understand the metabolic profiles of ovarian cancer, we utilized patient-derived xenografts (PDXs) derived from high-grade serous ovarian carcinoma (HGSOC), and performed comprehensive analysis of metabolic pathways by Reverse Phase Protein Array (RPPA). The RPPA analysis revealed PDX subsets with high or low mitochondrial activity and metabolism, and we identified succinate dehydrogenase (SDHA) to be a top differentially expressed metabolic protein between those PDX subsets. SDHA is a mitochondrial enzyme that participates in the TCA cycle and the electron transport chain, which are both essential for cellular metabolism. Analysis of the TCGA data demonstrated that SDHA gene alterations are highly prevalent in HGSOC patients (19% cases). Despite these findings, the impact of SDHA amplification on cancer biology is poorly understood. To assess the effect of SDHA overexpression on energy metabolism, we used SDHA-overexpressing ovarian cancer cell lines and measured cellular respiration by Seahorse. The results revealed that the overexpression of SDHA leads to a significant increase in basal and maximal respiration shifting cellular metabolism towards increased oxidative phosphorylation in mitochondria. Further, we determined if SDHA overexpression redirects cellular metabolism in response to deprivation of selected nutrients. In the conditions with low glucose or glutamine, SDHA overexpressing cells significantly increased basal respiration when compared with controls. In galactose medium that disrupts glycolysis, the SDHA lost its ability to induce cellular respiration, which indicates that SDHA relays on glycolysis to increase mitochondrial respiration. Together, our data indicate that SDHA requires glycolysis to fuel TCA cycle and and support cellular respiration. Next, we performed in vitro drug screening and found that SDHA overexpressing cells are highly sensitive to glycolysis inhibitor Shikonin. Our pilot in vivo data showed that Shikonin significantly reduces growth of SDHA-amplified tumors. In summary, our studies indicate that SDHA upregulation plays a role in reprogramming of cellular metabolism and pathogenesis of ovarian cancer. Moreover, the unique metabolic state of ovarian cancer associated with SDHA amplification could be successfully targetable offering a potential new treatment strategy for ovarian cancer patients. Citation Format: Magdalena Cybula, Maria Rostworowska, Lin Wang, Summer Wang, Ana Luiza Drumond-Bock, Magdalena Bieniasz. The role of succinate dehydrogenase in ovarian cancer metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB125.