Resveratrol suppresses cancer cell glucose uptake by targeting reactive oxygen species-mediated hypoxia-inducible factor-1α activation.
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-1α (HIF-1α), 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-1α protein was markedly reduced by resveratrol, and inhibiting HIF-1α expression with cycloheximide or specific small interfering RNAs suppressed (18)F-FDG uptake. The proteosomal inhibitor MG132 partly restored HIF-1α 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.


CONCLUSIONS
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-1α accumulation.
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Kyung-Ho
KH
Jung
Jin Hee
JH
Lee
Cung Hoa
CH
Thien Quach
Jin-Young
JY
Paik
Hyunhee
H
Oh
Jin Won
JW
Park
Eun Jeong
EJ
Lee
Seung-Hwan
SH
Moon
Kyung-Han
KH
Lee
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019344:Lactic Acid / Q000096:biosynthesis; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*
D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D013267:Stilbenes; D019788:Fluorodeoxyglucose F18; D019344:Lactic Acid; D005947:Glucose; D000077185:Resveratrol
18F-FDG; HIF-1α; cancer; reactive oxygen species; resveratrol