Abstract GMM-049: STAT3 PROMOTES OVARIAN CANCER GROWTH AND DRUG RESISTANCE BY MODULATING THE ENERGY METABOLISM

Abstract

Abstract Signal Transducers and Activators of Transcription 3 (STAT3) is a transcription factor that is known to play a key role in cancer progression. In ovarian cancer, STAT3 overexpression leads to increased cancer cell proliferation and confers resistance to chemotherapy-induced apoptosis in epithelial malignancies. It is constitutively activated in patient-derived ovarian cancer cells and a predictor of poor prognosis. Apart from its function as a transcription factor, recently STAT3 has been shown to translocate to mitochondria facilitated by phosphorylation at S727 and modulate mitochondrial function to promote carcinogenesis. Our study aimed to investigate if STAT3 overexpression can modulate cellular metabolism and promote the growth of ovarian cancer cells. We generated stable clones overexpressing STAT3 in A2780 ovarian cancer cells, along with empty vector clones. Ectopic expression of STAT3 in A2780 resulted in increased proliferation, colony formation ability and chemoresistance in vitro and led to large and aggressive ovarian tumors compared to parental and vector controls in xenograft mouse model. STAT3 overexpressing clones exhibited higher mitochondrial respiration and glycolysis placing them in the ‘metabolically active' phenotype compared to parental and vector clones (metabolically less active phenotype). A selective inhibitor of STAT3, Stattic, inhibited both nuclear and mitochondrial STAT3 and also attenuated the STAT3 mediated growth of over-expressing clones both in vitro and in vivo. Stattic treatment also reversed the STAT3-mediated chemoresistance. In contrast, a selective inhibitor of STAT3-Y705, Cryptotanshinone was relatively less effective. Also, Stattic treatments reversed the ‘metabolically active’ state of STAT3 overexpressing clones to a ‘lower metabolic state,’ as the control cells. Stattic also inhibited the cell proliferation and modulated bioenergetic phenotype of other ovarian cancer cells lines (PEO4, C200, and OVCAR3) that display a metabolically active phenotype suggesting STAT3 plays a vital role in attaining a metabolically active phenotype by cancer cells. Although, an increase in mitochondrial function was observed in overexpressing A2780 clones as evident from enhanced oxidative phosphorylation, there is no change in the mitochondrial mass or number in overexpressing clones compared to parental A2780 and vector clones indicating the critical role of STAT3 in mitochondrial functions rather than mitochondrial biogenesis in ovarian cancer cells. Further, evaluation of expression and function of mitochondrial STAT3 in ovarian cancers is warranted. Overall, STAT3 can induce metabolic changes in ovarian cancer cells by facilitating mitochondrial function, maybe as a survival mechanism and enhances the cellular fitness of the ovarian cancer cell resulting in increased oncogenic abilities. Citation Format: Vaishnavi Raja, Shailendra Giri, Suhail Hamid, Adnan R Munkarah and Ramandeep Rattan. STAT3 PROMOTES OVARIAN CANCER GROWTH AND DRUG RESISTANCE BY MODULATING THE ENERGY METABOLISM [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-049.