Garcinol modulates tyrosine phosphorylation of FAK and subsequently induces apoptosis through down-regulation of Src, ERK, and Akt survival signaling in human colon cancer cells.
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.
Liao
Chiung-Ho
CH
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Sang
Shengmin
S
Ho
Chi-Tang
CT
Lin
Jen-Kun
JK
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D015536:Down-Regulation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D061965:Matrix Metalloproteinase Inhibitors; D010936:Plant Extracts; D013729:Terpenes; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; C054597:garcinol