Garcinol, from the fruit rind of Garcinia indica and other species, has been reported to suppress colonic aberrant crypt foci (ACF) formation in rats. In this study, we investigate the beneficial effects of tumor prevention by garcinol on the human colorectal cancer cell line, HT-29. Focal adhesion kinase (FAK) is the major signaling mediator of integrin-mediated cell-matrix contact-regulated cellular proliferation, migration, and apoptosis in adherent cells. Results of Matrigel analysis show that exposure of HT-29 cells to 10 microM garcinol inhibited cell invasion, and decreased the dose-dependent tyrosine phosphorylation of FAK. We further demonstrate by Western blot analysis that garcinol inhibited activation of the Src, MAPK/ERK, and PI3K/Akt signaling pathways. To investigate whether the loss of integrin-mediated cell-matrix contact can induce apoptosis, we demonstrate that garcinol induced it in HT-29 cells. The apoptotic dose of garcinol (20 microM) changed the ratio of the anti-apoptotic Bcl-2 and proapoptotic BAX proteins within 12 h, which correlated with a release of cytochrome c from the mitochondria to the cytosol, and with PARP cleavage. Additionally, we demonstrate that a decreasing MMP-7 protein level in HT-29 cells results in sensitization to garcinol. Garcinol also significantly inhibited the expression of MMP-7 in IL-1beta-induced HT-29 cells. These results suggest that garcinol reduces cell invasion and survival through the inhibition of FAK's downstream signaling.
Propolis, a natural product collected by honeybee, has been reported to exert a wide spectrum of biological functions. In this study, we have isolated a novel component, namely, propolin H, and investigated its effects in human carcinoma cells. Propolin H inhibited the proliferation of human lung carcinoma cell lines in MTT assay, and a significant G1 arrest was observed to occur in a dose-dependent manner at 24 h of exposure in H460 cells. After treatment with propolin H in H460 cells, the content of the CDK inhibitor p21Waf1/Cip1 protein increased in correlation with the elevation in p53 levels. Western blot analysis of G1 regulatory proteins further revealed a decrease in cyclin-dependent kinase 2 (CDK2) and CDK4 and an increase in cyclin E. The CDKs kinase activities assay showed that propolin H has inhibited CDK2 and CDK4 kinase activities. Accordingly, coimmunoprecipitations revealed an increased association of both CDK2 and CDK4 immunoreactive protein with the p21Waf1/Cip1 protein complex under propolin H-treated conditions. Additionally, we found that propolin H enhanced the expression of p21Waf1/Cip1 in p53-mutant and p53-null lung carcinoma cell lines, following the induction of G1 arrest. Together, these findings suggest that the induction of p21Waf1/Cip1 expression occurred through p53-dependent and -independent pathways in propolin H-treated cells. Propolin H exerts its significantly growth inhibitory effects and may have therapeutic applications.
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