Molecular mechanism of 18F-FDG uptake reduction induced by genipin in T47D cancer cell and role of uncoupling protein-2 in cancer cell glucose metabolism

Abstract

IntroductionCompounds that modulate cancer cell glucose metabolism could open new opportunities for antitumor therapy and for monitoring response using 18F-FDG PET. Genipin, a natural dietary compound that blocks uncoupling protein 2 (UCP2)-mediated mitochondrial proton leakage, is a potential anticancer agent. We investigated the effect of genipin on glucose metabolism and the mitochondrial function of cancer cells. MethodsBreast and colon cancer cells were assessed for effects of genipin on 18F-FDG uptake. T47D breast cancer cells were further evaluated for time-dependent and dose-dependent effects on 18F-FDG uptake, lactate release, oxygen consumption rate (OCR), reactive oxygen species (ROS) production, and mitochondrial membrane potential. The effects of UCP2 knockdown were evaluated using specific siRNA. ResultsCancer cells displayed significant reductions in 18F-FDG uptake by genipin. T47D cells showed the greatest reduction to 32.6±1.0% of controls by 250μM genipin. The effect occurred rapidly, reaching a plateau by 1h that lasted up to 24h. The effect was dose-dependent with a half-inhibitory concentration of 60.8μM. An accompanying decrease in lactate release was consistent with reduced glycolytic flux. OCR was significantly decreased by genipin to 82.2±11.4% of controls, and ROS generation was increased to 156.7±16.0%. These effects were largely reproduced by UCP2 knockdown with specific siRNA. ConclusionsGenipin decreased cancer cell 18F-FDG uptake by reducing both glycolytic flux and mitochondrial oxidative respiration. This effect appeared to occur by blocking the ability of UCP2 to dissipate energy and restrict ROS production through proton leakage.