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
gamma-tocotrienol, a
natural product commonly found in
palm oil and rice bran, on the accumulation of HIF-1alpha
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 micromol/L for 24h. Both basal level and
cobalt(II) chloride-induced HIF-1alpha
protein accumulation and
VEGF paracrine secretion were inhibited in SGC-7901 cells treated with
gamma-tocotrienol at 60 micromol/L treatment for 24 h.
U0126, a MEK1/2 inhibitor, decreased the expression of HIF-1alpha
protein and the paracrine secretion of
VEGF under normoxic and hypoxic conditions. In this study,
gamma-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-1alpha
protein accumulation and
VEGF secretion. These data suggest that HIF-1alpha/
VEGF could be a promising target for
gamma-tocotrienol in an effective method of
chemoprevention and
chemotherapy in human
gastric cancer.