Quercetin-induced apoptotic cascade in cancer cells: Antioxidant versus estrogen receptor α-dependent mechanisms

The flavonol quercetin, especially abundant in apple, wine, and onions, is reported to have anti-proliferative effects in many cancer cell lines. Antioxidant or pro-oxidant activities and kinase inhibition have been proposed as molecular mechanisms for these effects. In addition, an estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity plays a role in the quercetin-induced anti-proliferative effects. Here, we studied the molecular mechanisms of quercetin committed to the generation of an apoptotic cascade in cancer cells devoid or containing transfected estrogen receptor a (ER alpha; i.e., human cervix epitheloid carcinoma HeLa cells). Although none of tested quercetin concentrations increase reactive oxygen species (ROS) generation in HeLa cells, quercetin stimulation prevents the H2O2-induced ROS production both in the presence and in the absence of ER alpha. However, this flavonoid induces the activation of p38/MAPK, leading to the proapoptotic caspase-3 activation and to the poly(ADP-ribose) polymerase cleavage only in the presence of ER alpha. Notably, no down-regulation of survival kinases (i.e., AKT and ERK) was reported. Taken together, these findings Suggest that quercetin results in HeLa cell death through an ER alpha-dependent mechanism involving caspase- and p38 kinase activation. These findings indicate new potential chemopreventive actions of flavonoids on cancer growth.