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

INTRODUCTION

Compounds that modulate cancer cell glucose metabolism could open new opportunities for antitumor therapy and for monitoring response using (18)F-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.

METHODS

Breast and colon cancer cells were assessed for effects of genipin on (18)F-FDG uptake. T47D breast cancer cells were further evaluated for time-dependent and dose-dependent effects on (18)F-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.

RESULTS

Cancer cells displayed significant reductions in (18)F-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.

CONCLUSIONS

Genipin decreased cancer cell (18)F-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.