γ-Tocotrienol modulates the paracrine secretion of VEGF induced by cobalt(II) chloride via ERK signaling pathway in gastric adenocarcinoma SGC-7901 cell line

Abstract

Hypoxia is a common characteristic feature of solid tumors, and carcinoma cells are known to secrete many growth factors. These growth factors, such as vascular endothelial growth factor (VEGF), play a major role in the regulation of tumor angiogenesis and metastasis. In this study, the effect of γ-tocotrienol, a natural product commonly found in palm oil and rice bran, on the accumulation of HIF-1α protein and the paracrine secretion of VEGF in human gastric adenocarcinoma SGC-7901 cell line induced by cobalt(II) chloride (as a hypoxia mimic) was investigated. These results showed that cobalt(II) chloride induced the high expression of VEGF in SGC-7901 cells at dose of 150 μmol/L for 24 h. Both basal level and cobalt(II) chloride-induced HIF-1α protein accumulation and VEGF paracrine secretion were inhibited in SGC-7901 cells treated with γ-tocotrienol at 60 μmol/L treatment for 24 h. U0126, a MEK1/2 inhibitor, decreased the expression of HIF-1α protein and the paracrine secretion of VEGF under normoxic and hypoxic conditions. In this study, γ-tocotrienol also significantly inhibited the hypoxia-stimulated expression of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2). The mechanism seems to involve in inhibiting hypoxia-mediated activation of p-ERK1/2, it leads to a marked decrease in hypoxia-induced HIF-1α protein accumulation and VEGF secretion. These data suggest that HIF-1α/VEGF could be a promising target for γ-tocotrienol in an effective method of chemoprevention and chemotherapy in human gastric cancer.