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

Abstract

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.

Garcinol, a Polyisoprenylated Benzophenone Modulates Multiple Proinflammatory Signaling Cascades Leading to the Suppression of Growth and Survival of Head and Neck Carcinoma

“…Although previous studies have shown that garcinol can modulate AKT survival signaling cascade in colorectal cancer cells (12), our study is also the first report to examine the effect of garcinol on AKT/mTOR/S6K1 signaling axis in HNSCC cells. We found that garcinol treatment suppressed the expression of phospho-AKT, -mTOR, and -S6K1 in a time-dependent manner in CAL27 cells, which further indicates the possibility that garcinol could interfere with the mTOR-rictor complex that phosphorylates AKT at Ser 473.…”

“…Garcinol has gained much attention in the field of cancer research in recent years, and several reports have shown the antineoplastic and chemopreventive role of garcinol in different cancers, such as leukemia, colorectal, gastrointestinal, and breast cancers (12)(13)(14)(15)(16). Although there is a prior evidence showing that garcinol can inhibit 4-nitroquinoloine 1-oxide-induced tongue carcinogenesis (17), mechanisms through which garcinol elicits its antitumor activity, specifically in HNSCC, is unknown till date.…”

Focal Adhesion Kinase Expression in Human Neuroblastoma: Immunohistochemical and Real-time PCR Analyses

“…It is possible that FAK expression is up-regulated by the neuroblastoma tumors to maintain survival as the tumor proceeds from anchorage-dependent to anchorage-independent growth and metastasis. FAK has also been shown in other human tumors to have antiapoptotic properties through the up-regulation of the phosphatidylinositol 3-kinase-Akt pathway with subsequent increases in the antiapoptotic Bcl-2 protein and decreases in the proapoptotic protein Bax (6,[30][31][32]. In neuroblastoma, increased expression of Bcl-2 and decreased expression of Bax have been shown to correlate with poorer prognosis (33,34) and decreased sensitivity to chemotherapeutic drugs (35).…”

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

“…In rats, garcinol protects against 4-nitroquinoline-1-oxide-induced tongue carcinogenesis [2] and azoxymethane-induced colon carcinogenesis [3]. Functional investigations have revealed anti-oxidative [4], anti-proliferative [5], proapoptotic [6], anti-invasive [7], and anti-inflammatory properties of garcinol [6,8,9].…”