Abstract
3893
The Rho GTPase-activating protein DLC-1 (deleted in liver cancer) is frequently down-regulated or silenced in various types of cancer cells and operates as a bona fide tumor suppressor gene in breast, liver and lung cancer. Restoration of DLC-1 expression by transfer of the DLC-1 gene in human tumor cells that do not express the endogenous gene suppresses tumor cells proliferation in vitro and tumorigenicity in vivo. Several types of antioncogenic factors also augment the expression of the DLC-1 gene. We examined the effect of 2-phenyl-4H-1-benzopyran-4-one (flavone), a proapoptotic dietary constituent, on 11 breast, colon, liver, and prostate cell lines cell lines lacking or expressing low levels of DLC-1 mRNA. A 24 -hrs treatment with 150-mM flavone induced DLC-1 expression in four cell lines derived from metastatic or aggressive breast carcinoma and one colon carcinoma cell line but had no effect in normal breast cells, liver and prostate carcinoma cells. The induction of DLC-1 expression was associated with G2 arrest/apoptosis and p53 mutation or deletion. Generally, cell cycle arrest was accompanied by increased p21 mRNA. However, increased p21 protein expression was observed only in those cells arrested in G2 that exhibited elevated p53 protein. Flavone induction of apoptosis was p53-dependent or independent according to specific cell lines. Suppression of cell proliferation and G1 cell arrest associated with flavone-induced expression of DLC-1 in certain lines occurred in the absence of p21 activation. Collectively the current observations are consistent with the notion that flavone affects the expression of genes involved in cancer cell growth regulation and apoptosis. An important observation is that among various types of cancer cells, flavone was most effective in inducing the expression of DLC-1 gene in breast cancer cell lines. Since breast carcinoma cell lines responsive to flavone lack DLC-1 expression because of promoter hypermethylation, demethylation of tumor suppressor genes probably due to partial inhibition of DNA methyltrasferase may be an important epigenetic mechanism contributing to the chemopreventive activity of flavones. In combination with demetylating agents, flavone can be more effective in reactivating methylation-silenced genes.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]