Resveratrol slows cell growth by targeting the Warburg effect and stimulating mitochondria metabolism

Abstract

Resveratrol (RES) is a plant-derived polyphenol that has been widely studied due to its health promoting effects, which are associated with RES ability to positively impact mitochondria function. Here, I investigated the interaction between RES’s effects on growth and metabolism in PC3 prostate cancer cells and demonstrated that RES-mediated growth inhibition is coincidental with an increase in mitochondrial network fusion, biogenesis and cellular respiration. This indicates that a metabolic reprogramming towards oxidative phosphorylation might be essential for RES antiproliferative effects. Indeed, when RES-induced metabolic reprogramming was prevented either by growing cells in galactose or stabilizing hypoxia inducible factor-1α (HIF-1α) expression, RES effects on growth and metabolism were attenuated or even abolished. Furthermore, consistent with RES ability to reduce HIF-1α levels, I observed that RES’s cell growth inhibitory effects were enhanced under hypoxia. This denotes the importance of conducting in vitro studies under conditions that better represent the physiological environment. However, , most in vitro studies are performed at supraphysiological levels of oxygen (O2) (18% O2; compared to the usual 1-5% O2 range observed in vivo) and glucose (25mM, which is close to five-times higher than normal plasma (glucose) in a healthy human). This artificial environment can affect a wide variety of cellular activities that may compromise in vitro studies’ reliability. It is therefore important to determine how cell culture conditions might affect RES in vitro effects. This was achieved by growing PC3 human prostate cancer and C2C12 mouse myoblasts cells under different culture conditions: physiological O2 (here considered 5% O2) and glucose levels (5mM); physiological O2 and high glucose (25mM); supraphysiological O2 (18% O2) and high glucose (25mM). Overall, RES effects on cell proliferation and mitochondrial network were less effective when cells were grown at 5% O2 and 5mM glucose (media condition that best resembles the physiological environment). In conclusion, these findings demonstrate the importance of oxygen and glucose levels as key determinants of RES in vitro antiproliferative effects, which may contribute to the discrepancy observed for resveratrol’s effects both in vivo and in vitro.