Abstract 378: Stat3 promotes ovarian cancer by modulating the energy metabolism and develops drug resistance in patients

Abstract

Abstract Signal Transducers and Activators of Transcription (STAT) are a group of transcription factors that are known to play a major role in cancer progression. In ovarian cancer, increased STAT3 leads to cancer proliferation in response to cytokines and confers resistance to chemotherapy-induced apoptosis in epithelial malignancies. STAT3 is constitutively activated in patient derived ovarian cancer cells, and increased STAT3 expression is a predictor of poor prognosis. Apart from its function as a transcription factor, recently STAT3 has been shown to modulate mitochondrial function to promote carcinogenesis. The aim of our study was to investigate if STAT3 activation can modulate cellular metabolism of ovarian cancer cells. Stable clones expressing STAT3 were generated in A2780 ovarian cancer cells, along with empty vector clones. Ectopic expression of STAT3 in A2780 ovarian cancer cell line resulted in increased proliferation (p<0.01) and colony formation ability (p<0.001) in vitro and led to large ovarian tumors (p<0.01) compared to parental and vector controls in xenograft mouse model. Bioenergetics profiling showed higher mitochondrial respiration (OCR) and glycolysis (ECAR) in STAT3 clones compared to parental and vector clones. Ratio of ECAR/OCR in the STAT3 overexpressing cells placed them in the ‘metabolically active' phenotype, while parental A2780 and vector clones were in ‘metabolically less active' phenotype. A selective inhibitor of STAT3, STATTIC, inhibited the STAT3 mediated growth of A2780 cells both in vitro (p<0.01) and in vivo (p<0.01). In addition, STATTIC treatments reversed the ‘metabolically active' state of STAT3 overexpressing clones to a ‘lower metabolic state', placing them in the same category as the control cells. In addition, STATTIC inhibited the cell proliferation and modulated bioenergetic phenotype of other ovarian cancer cells lines (PEO4, C200 and OVCAR3) that display a ‘metabolically active' phenotype. Overall, STAT3 can induce metabolic changes in ovarian cancer cells, maybe as survival mechanism and enhances the cellular fitness of the ovarian cancer cell resulting in increased oncogenic abilities. Citation Format: Vaishnavi Raja, Shailendra Giri, Sharif Sakr, Miriana Hijaz, Raymond Quiles, Adnan R. Munkarah, Ramandeep Rattan. Stat3 promotes ovarian cancer by modulating the energy metabolism and develops drug resistance in patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 378.