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.