Abstract A69: Role of mitochondrial-STAT3 in promoting chemoresistance by modulating the energy metabolism in ovarian cancer

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 mitochondrial-STAT3, rather than nuclear-STAT3, plays a major role in modulating cellular metabolism and promoting chemoresistance in 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 the 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 STAT3 inhibitor, Stattic, inhibited both nuclear and mitochondrial STAT3 and also attenuated the STAT3-mediated growth of overexpressing 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. Further, silencing STAT3-Y705 (nuclear-STAT3) did not significantly affect the chemoresistance, while silencing STAT3-S727 (mitochondrial-STAT3) reversed chemoresistance. Although an increase in mitochondrial function was observed in overexpressing A2780 clones as evident from enhanced oxidative phosphorylation, there was no change in the mitochondrial mass or number, indicating the critical role of STAT3 in mitochondrial function rather than mitochondrial biogenesis in ovarian cancer cells. Thus, further evaluation of expression and function of mitochondrial STAT3 in ovarian cancers is warranted. Overall, mitochondrial-STAT3 can induce metabolic changes in ovarian cancer cells and enhance their cellular fitness by promoting chemoresistance. Citation Format: Vaishnavi Raja, Shailendra Giri, Suhail Hamid, Thomas Buekers, Adnan Munkarah, Ramandeep Rattan. Role of mitochondrial-STAT3 in promoting chemoresistance by modulating the energy metabolism in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A69.