Resveratrol Suppresses Cancer Cell Glucose Uptake by Targeting Reactive Oxygen Species–Mediated Hypoxia-Inducible Factor-1α Activation

Abstract

Resveratrol is gaining attention for its anticancer effects and is also recognized for its antioxidant properties and influence on glucose metabolism. Augmented reactive oxygen species (ROS) and high glycolytic flux are common characteristics of malignant cells. We thus evaluated the effect of resveratrol on cancer cell glucose metabolism and investigated the role of ROS in the response. Methods: Cancer cells were measured for cell content and 18 F-FDG uptake. Assays were performed for lactate production; hexokinase activity and intracellular ROS; and immunoblotting for hypoxia-inducible factor-1a (HIF-1a), Akt, mammalian target of rapamycin, and glucose transporter type 1 (Glut-1). Animal studies were performed with small-animal PET imaging of Lewis lung carcinoma tumor-bearing mice. Results: Resveratrol mildly decreased cell content and more pronouncedly suppressed 18 F-FDG uptake in Lewis lung carcinoma, HT-29 colon, and T47D breast cancer cells. Hence, 18 F-FDG uptake normalized to cell content was reduced to less than half of controls by 24-h exposure to resveratrol. This reduction was attributed to reduced glycolytic flux and Glut-1 expression. Resveratrol also decreased intracellular ROS in patterns that closely paralleled 18 F-FDG uptake. Scavenging of ROS with N-acetyl cysteine, but not inhibition of nicotinamide adenine dinucleotide phosphate oxidase, was sufficient to suppress 18 F-FDG uptake. Conversely, ROS inducers effectively reversed the metabolic response of resveratrol. HIF-1a protein was markedly reduced by resveratrol, and inhibiting HIF-1a expression with cycloheximide or specific small interfering RNAs suppressed 18 F-FDG uptake. The proteosomal inhibitor MG132 partly restored HIF-1a level and 18 F-FDG uptake in resveratrol-treated cells. Resveratrol also inhibited Akt activation; in addition, inhibitors and small interfering RNAs against phosphoinositide 3-kinase decreased 18 F-FDG uptake. Finally, small-animal PET results showed resveratrol treatment to suppress tumor 18 F-FDG uptake in vivo. Conclusion: Resveratrol suppresses cancer cell 18 F-FDG uptake and glycolytic metabolism in a manner that depends on the capacity of resveratrol to inhibit intracellular ROS, which downregulates HIF-1a accumulation. Ther e is recently growing interest in natural products as an addition to the repertoire of agents that may be beneficial in our battle against cancer (1). Resveratrol, a natural polyphenol compound found in such fruits as grapes and berries, has particularly gained intense attention for its promising anticancer effects (2). Initially recognized for its ability to inhibit carcinogenesis at multiple stages (3,4), resveratrol has since been found to exert significant antitumor effects including inhibition of growth (5-7), induction of apoptosis (6-8), and suppression of metastatic potential (9,10).Resveratrol is known to reduce energy expenditure in vivo, mimicking the effects of caloric restriction (11). Recently, several in vitro studies have described an inhibitory effect of resveratrol ...

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