Epithelial ovarian carcinoma is the leading cause of death among patients with gynecological cancers. The majority of ovarian cancer patients succumb to chemoresistant, recurrent disease. Chemoresistance is accompanied by resistance to apoptosis, and the identification of targeted therapies that circumvent these mechanisms would enhance our ability to treat this disease. The most common alteration in cellular metabolism in neoplastic cells involves upregulated glucose uptake. The molecular changes that accompany the glycolytic phenotype during carcinogenesis may be targets for cancer prevention and treatment. PI3K, Akt, and Tor are potent oncogenic activators of cell growth that also regulate cellular metabolism and autophagy. Resveratrol is a natural phytoalexin that has anti-neoplastic activities in multiple tumor types. We have found that resveratrol induces autophagocytic cell death and inhibits glucose uptake in ovarian cancer cells. In mammalian cells, autophagy is induced under starvation conditions. In response to nutrient deprivation, cells attempt to recycle, degrade, and utilize their own organelles as a source of energy. Eventually, if nutrient deprivation is sustained, the cell will undergo autophagic cell death. We hypothesize that because resveratrol induces cell death through a mechanism distinct from apoptosis, resveratrol treatment may provide a therapeutic advantage in the management of chemoresistant ovarian cancer. We have designed a series of studies to determine how resveratrol modulates the PI3K/Akt/Tor pathway and to characterize the molecular mechanism of resveratrol modulation of glucose uptake in ovarian cancer cells. Finally, we will determine the chemopreventive and/or therapeutic potential of resveratrol in an ovarian cancer animal model.

The studies we propose will provide important insights into how deregulation of glucose metabolism can contribute to the neoplastic transformation of ovarian epithelial cells. Targeting ovarian cancer through inhibition of glucose metabolism using resveratrol and other glycolytic inhibitors may ultimately have broad clinical benefit to ovarian cancer patients.