Resveratrol-induce s-phase delay in cell cycle depends on cell metabolism

Abstract

The effect of polyphenols in cell cycle progression of tumor cell lines is widely known. Among polyphenols, resveratrol (RSV) is a stilbenoid known to activate sirtuins and to show prolongevity effects (Baur et al., 2006). Treatment of tumor cell lines with RSV produces a dose-dependent S-phase delay starting as early as 6-12 hours of incubation. Cell cycle distribution seems to return to normal values with time and depends on the dose of RSV. This delay occurs in both cell lines expressing and lacking p53. However, in cell lines able to express p53, RSV increases its protein levels and also the levels of downstream targets such as p21. Although RSV is considered an antioxidant, treatment of HeLa cells with this compound increases ROS levels in a time and dose-dependent mechanism. Other polyphenols such as dicumarol also increase ROS levels and induce S-phase delay (Hernández et al, 2008). However, incubation of RSV-treated cells with antioxidants and superoxide dismutase mimetics did not block S-phase delay induced by this polyphenol. On the other hand, RSV has been shown to increase AMPK activity. Incubation of HeLa cells with an AiCAR, an AMPK ligand, induced S-phase delay in a similar way as RSV. In order to determine if AMPK activity is related to S-phase delay, we preincubated cells with an inhibitor of AMPK and further treated them with RSV. Unfortunately, the inhibitor was unable to block RSV-dependent Sphase delay. Further, A549 cells, that do not express LKB1, a necessary upstream regulator of AMPK, also suffered S-phase delay after RSV treatment indicating that AMPK seems to be not involved. Tumor cells show a more glycolitic metabolism whereas primary cell lines are more respiratory. MEFs were more resistant to RSV-induced cell cycle delay than HeLa or other tumor cells. We conditioned HeLa cells to grow under low glucose conditions (1 g/l). These cells showed a more respiratory metabolism in comparison with their counterparts cultured under high glucose conditions and also showed a higher resistance against RSV. Taken together, our results indicate that metabolic profile of cells is a key factor in RSV-induced cell cycle delay.