Quercetin, a ubiquitous bioactive plant flavonoid, has shown to exert a broad range of activities, such as apoptotic, antioxidant, and anti-inflammatory effects. Thus, flavonoids can mediate both cell protection and cell injury. Recently, quercetin has been reported to prevent the progression of emphysema in animal models through antioxidant and anti-inflammatory actions. These findings suggest that quercetin could be a potential treatment option for chronic obstructive pulmonary disease. Its clinical application, however, could be limited by the cytotoxicity of quercetin, and understanding of the apoptotic mechanisms of quercetin is a prerequisite to develop a therapeutic strategy with minimal cytotoxicity. We evaluated the apoptotic effect of quercetin and its molecular mechanisms in normal bronchial epithelial cells (BEAS-2B cells). Quercetin decreased the viability of BEAS-2B cells via apoptosis in a dose- and time-dependent manner. Quercetin activated JNK and increased the expression levels of c-Jun and p53-dependent Bax. Blockade of JNK activation by overexpression of dominant negative JNK1 suppressed apoptosis by quercetin via inhibition of caspase-3 activation and reduction of p53 and Bax expression. Simultaneously, quercetin inactivated glycogen synthase kinase (GSK)-3β, which is phosphatidylinositol 3-kinase/Akt dependent. Overexpression of a constitutively active GSK-3β mutant enhanced quercetin-induced JNK activation. In contrast, overexpression of enzymatically inert GSK-3β inhibited JNK activation, resulting in a suppression of apoptosis by quercetin. Taken together, the JNK-p53 pathway is involved in quercetin-induced apoptosis, and simultaneous inactivation of GSK-3β can attenuate apoptosis in normal bronchial epithelial cells.
Keywords: c-Jun NH2-terminal kinase/caspase-3; glycogen synthase kinase-3β; lung epithelial cells; p53/Bax; quercetin.