Curcumin suppresses proliferation and invasion in human gastric cancer cells by downregulation of PAK1 activity and cyclin D1 expression
Curcumin suppresses proliferation and invasion in human gastric cancer cells by downregulation of PAK1 activity and cyclin D1 expression
复制标题
姜黄素通过下调 PAK1 活性和细胞周期蛋白 D1 表达抑制人胃癌细胞的增殖和侵袭
DOI：
10.4161/cbt.8.14.8720
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发表时间：
2009-07-15
影响因子：
3.6
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Cai, Xin-Ze;Wang, Jian;Li, Feng
姜黄素(二阿魏酰甲烷)是一种天然的化学预防药物，已知可以抑制几种癌细胞的增殖。已有研究表明姜黄素是表皮生长因子受体(EGFR)酪氨酸激酶的有效抑制剂，但其对EGFR下游蛋白p21激活的蛋白1(PAK1)的抑制作用尚未明确。在本文中，我们发现姜黄素抑制了HER2的表达，并抑制了PAK1的活性，但不影响其表达。在胃癌细胞中沉默HER2表明，即使PAK1活性被EGF一过性增强，姜黄素仍然具有很强的抑制作用。需要强调的是，体外的激酶实验表明，姜黄素可以作为一种ATP竞争性抑制剂，这一点得到了计算机辅助分子模拟的支持。姜黄素还下调细胞周期蛋白D1mRNA和蛋白的表达，抑制细胞从G(1)期向S期的过渡。因此，姜黄素抑制了胃癌细胞的增殖和侵袭。总体而言，这些结果为姜黄素抑制胃癌细胞生长的机制和胃癌的潜在治疗策略提供了新的见解。
Curcumin (diferuloylmethane), is a natural chemopreventive agent known to inhibit the proliferation of several cancer cell lines. It has been previously demonstrated that curcumin is a potent inhibitor of EGF-receptor (EGFR) tyrosine kinase, but its inhibitive effect on p21-activated kinase 1 (PAK1), a downstream protein of EGFR, has not been defined. In this paper we found that curcumin repressed the expression of HER2 and inhibited the kinase activity of PAK1 without affecting its expression. Silencing HER2 in gastric cancer cells showed that even if PAK1 activity was transiently strengthened by EGF, curcumin still had a strong inhibitive effect. It should be emphasized that kinase assay in vitro showed that curcumin could act as an ATP-competitive inhibitor, which was supported by computer-aided molecular modeling. Curcumin also downregulated the mRNA and the protein expression of cyclin D1 and suppressed transition of the cells from G(1) to S phase. Therefore, curcumin inhibited the proliferation and invasion of gastric cancer cells. Overall, these results provided novel insights into the mechanisms of curcumin inhibition of gastric cancer cell growth and potential therapeutic strategies for gastric cancer.