Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer

// Hui Guo 1, 2, 4 , Yan Zhong 2, 3 , Amanda L. Jackson 2 , Leslie H. Clark 2 , Josh Kilgore 2 , Lu Zhang 1, 2, 4 , Jianjun Han 2, 5 , Xiugui Sheng 1 , Timothy P. Gilliam 2 , Paola A. Gehrig 2, 6 , Chunxiao Zhou 2, 6 , Victoria L. Bae-Jump 2, 6 1 Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan University, Jinan, P.R. China 2 Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA 3 Department of Gynecologic Oncology, Linyi Cancer Hospital, Linyi, P.R. China 4 School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Shandong, P.R. China 5 Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Jinan, P.R. China 6 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA Correspondence to: Victoria L Bae-Jump, e-mail: victoria_baejump@med.unc.edu Chunxiao Zhou, e-mail: czhou@med.unc.edu Keywords: ovarian cancer, everolimus, proliferation, mTOR, metabolon Received: October 13, 2015 Accepted: January 24, 2016 Published: March 05, 2016 ABSTRACT Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter-relationship between everolimus and obesity in vivo . Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro . Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers.