Abstract 4080: Metformin and rapamycin inhibit proliferation and alter glucose metabolism in endometrial and ovarian cancer cell lines

Abstract

Abstract Objectives: A well-established phenomenon of tumor cells is a shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, termed the “Warburg” effect. Glycolysis is a much less efficient mechanism of producing ATP, suggesting that cancer cells may have an inherently high need for rapidly metabolized glucose. Glucose metabolism and growth control are tightly linked in proliferating cells and involve signaling pathways such as the PI3K/Akt/mTOR pathway. Metformin and rapamycin both exert their anti-tumorigenic effects through inhibition of the PI3K/Akt/mTOR pathway. Thus, our goal was to investigate the mechanism of action of metformin and rapamycin on proliferation and glucose metabolism in vitro using both endometrial and ovarian cancer cell lines Methods: The endometrial cancer cell lines, ECC-1 and Ishikawa, and the ovarian cancer cell lines, CAOV-3 and SKOV-3, were used in these studies. Cell proliferation was assessed after exposure to metformin and rapamycin, and viable cell densities were determined by measuring conversion of the metabolic dye, MTT. Western immunoblotting was performed to determine the expression of the glucose transporters, GLUT1 and GLUT4, and phosphorylated glycogen synthase kinase-3 alpha and beta (GSK-α and GSK-β). Expression of phosphorylated S6, a downstream target of the mTOR pathway, was also evaluated by Western immunoblotting. Results: Metformin and rapamycin both potently inhibited growth in a dose-dependent manner in the endometrial and ovarian cancer cell lines (IC50 of 1-10 mM for metformin and IC50 of 5-18 nM for rapamycin). Metformin and rapamycin also stimulated expression of the glucose transporters, GLUT1 and GLUT4, and increased phosphorylation of GSK-α and GSK-β among the endometrial and ovarian cancer cell lines. In parallel, S6 phosphorylation was decreased after treatment with metformin and rapamycin. Conclusions: Metformin and rapamycin are both potent inhibitors of cell proliferation and potentially alter glucose metabolism in endometrial and ovarian cancer cells. These findings suggest that metformin and rapamycin may have two interrelated anti-tumorigenic benefits – inhibition of the PI3K/Akt/mTOR pathway and disruption of glucose uptake and utilization by tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4080. doi:10.1158/1538-7445.AM2011-4080