Antiproliferative Effect of γ-Mangostin in Gastric Cancer Cells is Mediated by c-Met Signaling Pathway

초록

Encoding the receptor for hepatocyte growth factor (HGF), the proto-oncogene c-Met represents one of the tyrosine kinases most commonly found to be dysregulated across human cancers, and has consequently emerged as a promising target for anticancer drug discovery. γ-Mangostin, one of the major bioactive constituents of mangosteen (Garcinia mangostana L.), is known to regulate a range of cancer-related signaling pathways. MKN45 gastric cancer cell line, harboring c-Met amplification, were treated with γ-mangostin and evaluated by western blot, cell viability and apoptosis assays. We further confirmed that γ-mangostin treatment modulates the expression of c-Myc, cyclin D1, and p21, and suppresses the activity of pro-survival proteins, specifically Bcl-2 and Bcl-xL, through downregulation of c-Met. γ-Mangostin suppressed cell proliferation in MKN45 with an IC50 values 32.6 μM. Relative to untreated controls, γ-mangostin exposure led to elevated p21 Waf1/Cip1 levels and reduced expression of c-Myc, CD44, and cyclin D1. In addition, γ-mangostin suppressed the constitutive phosphorylation of c-Met, as well as that of its downstream signaling proteins ERK1/2 and STAT3. Antioncogenic and apoptotic effects (c-Myc, p21 Waf1/Cip1 and Caspase-3) by γ–mangostin treatment are mediated by c-Met inactivation. In conclusion, these observations indicate the potential of γ–mangostin as an effective antitumor agent against gastric adenocarcinoma. In addition, these results suggest that the compound's antitumor activity is mediated, at least in part, through suppression of c-Met signaling.

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