p53-Independent Apoptosis Induced by Genistein in Lung Cancer Cells

Abstract

Lung cancer is the leading cause of cancer-related deaths in the world, with increasing incidence in many developed countries. Epidemiological data suggest that consumption of soy products may be associated with a decreased risk of cancer. Despite the association of nutrition and cancer, the molecular mechanisms by which the active metabolite in the soy diet, genistein, exerts its biological response have not been studied. We previously showed that genistein can inhibit the growth of H460 non-small-cell lung cancer (NSCLC) cells in vitro. To explore the molecular mechanisms by which genistein inhibits the growth of NSCLC cells, we investigated cell growth inhibition, modulation in gene expression, and induction of apoptosis by genistein in H460 cells, which harbor wild-type p53, and H322 cells, which possess mutated p53. Genistein was found to inhibit H460 and H322 cell growth in a dose-dependent manner. Staining with 4,6-diamidino-2-phenylindole, poly(ADP-ribose) polymerase cleavage, and flow cytometric apoptosis analysis were used to investigate apoptotic cell death, and the results show that 30 μM genistein causes cell death via a typical apoptotic pathway. Western blot analysis demonstrated upregulations of p21^WAF1 and Bax by genistein in wild-type and mutant p53 cell lines. Furthermore, cells treated with genistein showed an increased expression of endogenous wild-type p53, while the level of the mutant p53 protein remained unchanged. From these results, we conclude that genistein induces apoptosis in NSCLC cells through a p53-independent pathway and, thus, may act as an anticancer agent.