Central Laboratory, The First Affiliated Hospital of Harbin Medical University, 23 YouZheng Street, NanGang District, Harbin 150001, People's Republic of China.
Toxicology. 2010 Jul-Aug;274(1-3):27-33. doi: 10.1016/j.tox.2010.05.002. Epub 2010 May 7.
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.
缺氧是实体肿瘤的常见特征，已知癌细胞会分泌许多生长因子。这些生长因子，如血管内皮生长因子 (VEGF)，在调节肿瘤血管生成和转移中起着重要作用。在这项研究中，研究了γ-生育三烯酚，一种在棕榈油和米糠中常见的天然产物，对氯化钴（作为缺氧模拟物）诱导的人胃腺癌 SGC-7901 细胞系中 HIF-1α 蛋白积累和 VEGF 旁分泌的影响。这些结果表明，氯化钴在 150μmol/L 剂量下诱导 SGC-7901 细胞中 VEGF 的高表达 24 小时。在 60μmol/L 处理 24 小时的 SGC-7901 细胞中，γ-生育三烯酚可抑制基础水平和氯化钴诱导的 HIF-1α 蛋白积累和 VEGF 旁分泌。U0126，一种 MEK1/2 抑制剂，可降低常氧和缺氧条件下 HIF-1α 蛋白的表达和 VEGF 的旁分泌。在这项研究中，γ-生育三烯酚还显著抑制了缺氧刺激的细胞外信号调节激酶 1/2 磷酸化 (p-ERK1/2) 的表达。该机制似乎涉及抑制缺氧介导的 p-ERK1/2 激活，导致缺氧诱导的 HIF-1α 蛋白积累和 VEGF 分泌明显减少。这些数据表明，HIF-1α/VEGF 可能是γ-生育三烯酚在人类胃癌化学预防和化疗中一种有前途的靶标。
