Increased efficacy of metformin corresponds to differential metabolic effects in the ovarian tumors from obese versus lean mice

// Jianjun Han 1, 2 , Weiya Z. Wysham 3 , Yan Zhong 2, 4 , Hui Guo 2, 5 , Lu Zhang 2, 5 , Kim M. Malloy 6 , Hallum K. Dickens 2 , Gene Huh 7 , Douglas Lee 8 , Liza Makowski 9, 10 , Chunxiao Zhou 2, 10 and Victoria L. Bae-Jump 2, 10 1 Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, Postdoctoral Mobile Station of Tianjin Medical University, Tianjin, P.R. China 2 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, USA 3 Legacy Medical Group, Gynecologic Oncology, Portland, OR, USA 4 Department of Gynecologic Oncology, Linyi Cancer Hospital, Linyi, Shandong, P.R. China 5 Department of Gynecologic Oncology, Shandong Cancer Hospital & Institute, Jinan, P.R. China 6 Virginia Tech/Carilion Clinic, Department of Obstetrics and Gynecology, Blacksburg, VA, USA 7 Seoul National University College of Medicine, Seoul, South Korea 8 Omic Insight, Durham, NC, USA 9 Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA 10 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA Correspondence to: Victoria L. Bae-Jump, email: victoria_baejump@med.unc.edu Chunxiao Zhou, email: czhou@med.unc.edu Keywords: metformin, metabolism, ovarian cancer, mTOR pathway, obesity Received: June 03, 2017      Accepted: August 03, 2017      Published: September 08, 2017 ABSTRACT Obesity is a significant risk factor for ovarian cancer (OC) and associated with worse outcomes for this disease. We assessed the anti-tumorigenic effects of metformin in human OC cell lines and a genetically engineered mouse model of high grade serous OC under obese and lean conditions. Metformin potently inhibited growth in a dose-dependent manner in all four human OC cell lines through AMPK/mTOR pathways. Treatment with metformin resulted in G1 arrest, induction of apoptosis, reduction of invasion and decreased hTERT expression. In the K18-gT 121 +/- ; p53 fl/ fl ; Brca1 fl/fl (KpB) mouse model, metformin inhibited tumor growth in both lean and obese mice. However, in the obese mice, metformin decreased tumor growth by 60%, whereas tumor growth was only decreased by 32% in the lean mice (p=0.003) compared to vehicle-treated mice. The ovarian tumors from obese mice had evidence of impaired mitochondrial complex 2 function and energy supplied by omega fatty acid oxidation rather than glycolysis as compared to lean mice, as assessed by metabolomic profiling. The improved efficacy of metformin in obesity corresponded with inhibition of mitochondrial complex 1 and fatty acid oxidation, and stimulation of glycolysis in only the OCs of obese versus lean mice. In conclusion, metformin had anti-tumorigenic effects in OC cell lines and the KpB OC pre-clinical mouse model, with increased efficacy in obese versus lean mice. Detected metabolic changes may underlie why ovarian tumors in obese mice have heightened susceptibility to metformin.