Curcumin Inhibition of Integrin (α6β4)-Dependent Breast Cancer Cell Motility and Invasion
Curcumin Inhibition of Integrin (α6β4)-Dependent Breast Cancer Cell Motility and Invasion
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DOI：
10.1158/1940-6207.capr-08-0087
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发表时间：
2008-10-01
影响因子：
3.3
通讯作者：
Chung, Jun
中科院分区：
文献类型：
--
作者：
Kim, Hong Im;Huang, Huang;Chung, Jun
姜黄素是一种从姜黄根茎中提取的多酚类天然产物，是一种很有前途的抗癌药物。然而，姜黄素抑制癌细胞功能如细胞生长、存活和细胞运动的机制在很大程度上是未知的。我们探讨了姜黄素是否影响整合素α（6）β（4）的功能，整合素α（6）β（4）是一种层粘连蛋白粘附受体，在癌细胞的侵袭和迁移中具有既定的作用。在这里，我们发现姜黄素以浓度依赖性方式显著降低α（6）β（4）依赖性乳腺癌细胞的运动性和侵袭性，而不影响MDA-MB-435/β 4（β（4）-整合素转染子）和MDA-MB-231乳腺癌细胞系的凋亡。此外，姜黄素选择性地减少β（4）整联蛋白（Y1494）的基础磷酸化，据报道，这在介导α（6）β（4）依赖性磷脂酰肌醇3-激酶活化和细胞运动中是必需的。与这一发现一致，姜黄素还阻断了MDA-MB-435/β 4细胞系中α 6 β 4依赖性Akt激活和细胞运动促进因子ENPP 2的表达。姜黄素与其他α（6）β（4）信号通路的药理学抑制剂联合使用的多模式方法显示出阻断乳腺癌细胞运动和侵袭的叠加效应。总之，这些发现表明姜黄素通过直接抑制α（6）β（4）整联蛋白的功能来抑制乳腺癌细胞的运动和侵袭，并表明姜黄素可以作为过表达α（6）β（4）的肿瘤的有效治疗剂。
Curcumin, a polyphenol natural product isolated from the rhizome of the plant Curcuma longa, has emerged as a promising anticancer therapeutic agent. However, the mechanism by which curcumin inhibits cancer cell functions such as cell growth, survival, and cell motility is largely unknown. We explored whether curcumin affects the function of integrin alpha(6)beta(4), a laminin adhesion receptor with an established role in invasion and migration of cancer cells. Here we show that curcumin significantly reduced alpha(6)beta(4)-dependent breast cancer cell motility and invasion in a concentration-dependent manner without affecting apoptosis in MDA-MB-435/beta 4 (beta(4)-integrin transfectants) and MDA-MB-231 breast cancer cell lines. Further, curcumin selectively reduced the basal phosphorylation of beta(4) integrin (Y1494), which has been reported to be essential in mediating alpha(6)beta(4)-dependent phosphatidylinositol 3-kinase activation and cell motility. Consistent with this finding, curcumin also blocked alpha(6)beta(4)-dependent Akt activation and expression of the cell motility-promoting factor ENPP2 in MDA-MB-435/beta 4 cell line. A multimodality approach using curcumin in combination with other pharmacologic inhibitors of alpha(6)beta(4) signaling pathways showed an additive effect to block breast cancer cell motility and invasion. Taken together, these findings show that curcumin inhibits breast cancer cell motility and invasion by directly inhibiting the function of alpha(6)beta(4) integrin, and suggest that curcumin can serve as an effective therapeutic agent in tumors that overexpress alpha(6)beta(4).