Resveratrol Integrates Metabolic and Growth Effects in PC3 Prostate Cancer Cells-Involvement of Prolyl Hydroxylase and Hypoxia Inducible Factor-1

Resveratrol (RES) is a polyphenol produced by certain plant species that has been well studied due to its ability to slow the growth of cancer cells. In numerous cell types and tissues, RES has been demonstrated to promote mitochondrial biogenesis, fusion, and oxidative phosphorylation. The present study investigated the interaction between RES's effects on growth and metabolism in PC3 prostate cancer cells, and demonstrated that RES-mediated growth inhibition is only observed under conditions in which a metabolic shift from glucose fermentation to mitochondrial respiration can occur. When this shift was prevented by growing cells in galactose medium or by pharmacologically inhibiting prolyl hydroxylase (PHD) in order to stabilize hypoxia inducible factor-1, RES did not effect mitochondrial fusion, biogenesis, respiration or cell growth. Similar results were observed in PC3 cells expressing a mutant HIF-1 lacking the prolines that are hydroxylated by PHD to promote its degradation. Thus, RES appears to slow PC3 cell growth by interfering with glucose fermentation and promoting respiration. Consistent with this, RES was observed to be particularly effective at inhibiting PC3 cell growth under hypoxic conditions that precluded increased reliance on oxidative phosphorylation. These observations are important in understanding how RES may affect cancer cell growth in vivo where hypoxia is common in growing tumours.