Resveratrol inhibits glucose metabolism in human ovarian cancer cells.
OBJECTIVE
Resveratrol is a phytoalexin found in grapes that inhibits the in vitro growth of multiple tumor cell types. We showed previously that resveratrol induces autophagic cell death in ovarian cancer cells. Because autophagy is typically an adaptive response to nutrient starvation, we hypothesized that autophagy would also be triggered when ovarian cancer cells are nutrient deprived and that resveratrol could in fact be acting by inducing a starvation-like signaling response.


METHODS
Ovarian cancer cells were incubated with normal media, media containing resveratrol, glucose free media, or media lacking amino acids. Growth inhibition was determined using the sulforhodamine assay. Cells were evaluated for autophagocytosis by analyzing cleavage of LC3. Glucose uptake, lactate production, and activation of glycolytic regulators pAkt and pmTOR were analyzed following resveratrol treatment.


RESULTS
We show here that epithelial ovarian cancer cells are highly sensitive to glucose-deprivation-induced cell death and like resveratrol, glucose deprivation induces caspase-independent cell death with hallmarks of autophagy. Consistent with the hypothesis that resveratrol treatment results in biochemical conditions that mirror a nutrient deprived state, we found that resveratrol dramatically reduces glucose uptake and lactate production. Moreover, resveratrol reduces the levels of phosphorylated Akt and mTOR, two signals that increase glucose uptake and the rate limiting steps in glycolysis.


CONCLUSIONS
Our findings are consistent with the hypothesis that resveratrol-induced changes in glucose utilization comprise the mechanism that underlies resveratrol-induced autophagocytosis in ovarian cancer. Inhibition of glycolysis in ovarian cancer with resveratrol or other compounds may be effective therapy for ovarian cancer.
Kueck
Angela
A
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan, L4000 Women's Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Opipari
Anthony W
AW
Griffith
Kent A
KA
Tan
Lijun
L
Choi
Milheon
M
Huang
Jennifer
J
Wahl
Heather
H
Liu
J Rebecca
JR
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000493:pharmacokinetics; D005260:Female; D005947:Glucose / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014316:Tritium