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.
Highlights
Ovarian cancer is the most lethal gynecologic malignancy among women, with an anticipated 21,290 new cases and 14,180 deaths anticipated for 2015 in the United States [1]
Given that the PI3K/AKT/mTOR pathway is frequently activated in ovarian cancer and obesity, this study aimed to access the anti-tumorigenic efficacy of everolimus in ovarian cancer cells under different glucose conditions in vitro and in lean and obese mouse models of serous ovarian cancer in vivo
The mTOR pathway is a central regulator of various oncogenic processes that contribute to cell proliferation, cell cycle progression, metabolism, angiogenesis and drug resistance in a wide variety of cancers including ovarian cancer [16]
Summary
Ovarian cancer is the most lethal gynecologic malignancy among women, with an anticipated 21,290 new cases and 14,180 deaths anticipated for 2015 in the United States [1]. The standard treatment of ovarian cancer is surgical debulking combined with platinum-based combination chemotherapy. This therapeutic strategy has high initial response rates, the majority of patients are faced with a recurrence and chemoresistant disease [3]. Accumulating epidemiological evidence shows that obesity is associated with an increased risk of developing ovarian cancer compared with women of normal weight [4]. Obesity confers an increased risk of recurrence, challenges with chemotherapy dosing, and associated poor survival. This results in a 10–17% reduction in overall survival among obese women with ovarian cancer [4,5,6]. We have recently found that obesity promotes tumor aggressiveness in a genetically engineered mouse model of serous ovarian cancer [9]
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