Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
J Cell Physiol. 2019 Mar;234(3):2822-2836. doi: 10.1002/jcp.27100. Epub 2018 Aug 1.
Resveratrol, a natural polyphenol compound, has been shown to possess anticancer activity. However, how resveratrol inhibits cancer cell adhesion has not been fully elucidated. Here, we show that resveratrol suppressed the basal or type I insulin-like growth factor (IGF)-1-stimulated adhesion of cancer cells (Rh1, Rh30, HT29, and HeLa cells) by inhibiting the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway. Inhibition of Erk1/2 with U0126, knockdown of Erk1/2, or overexpression of dominant-negative mitogen-activated protein kinase kinase 1 (MKK1) strengthened resveratrol's inhibition of the basal or IGF-1-stimulated of Erk1/2 phosphorylation and cell adhesion, whereas ectopic expression of constitutively active MKK1 attenuated the inhibitory effects of resveratrol. Further research revealed that both protein phosphatase 2A (PP2A) and phosphatase and tensin homolog (PTEN)-Akt were implicated in resveratrol-inactivated Erk1/2-dependent cell adhesion. Inhibition of PP2A with okadaic acid or overexpression of dominant-negative PP2A rendered resistance to resveratrol's suppression of the basal or IGF-1-stimulated phospho-Erk1/2 and cell adhesion, whereas expression of wild-type PP2A enhanced resveratrol's inhibitory effects. Overexpression of wild-type PTEN or dominant-negative Akt or inhibition of Akt with Akt inhibitor X strengthened resveratrol's inhibition of the basal or IGF-1-stimulated Erk1/2 phosphorylation and cell adhesion. Furthermore, inhibition of mechanistic/mammalian target of rapamycin (mTOR) with rapamycin or silencing mTOR enhanced resveratrol's inhibitory effects on the basal and IGF-1-induced inhibition of PP2A-PTEN, activation of Akt-Erk1/2, and cell adhesion. The results indicate that resveratrol inhibits Erk1/2-mediated adhesion of cancer cells via activating PP2A-PTEN signaling network. Our data highlight that resveratrol has a great potential in the prevention of cancer cell adhesion.
白藜芦醇是一种天然多酚化合物，已被证明具有抗癌活性。然而，白藜芦醇如何抑制癌细胞黏附尚未完全阐明。在这里，我们发现白藜芦醇通过抑制细胞外信号调节激酶 1/2（Erk1/2）通路抑制基础或 I 型胰岛素样生长因子（IGF-1）刺激的癌细胞（Rh1、Rh30、HT29 和 HeLa 细胞）黏附。用 U0126 抑制 Erk1/2、敲低 Erk1/2 或过表达显性失活丝裂原活化蛋白激酶激酶 1（MKK1）增强白藜芦醇对基础或 IGF-1 刺激的 Erk1/2 磷酸化和细胞黏附的抑制作用，而组成型激活 MKK1 的异位表达则减弱白藜芦醇的抑制作用。进一步的研究表明，蛋白磷酸酶 2A（PP2A）和磷酸酶和张力蛋白同系物（PTEN）-Akt 都参与了白藜芦醇失活的 Erk1/2 依赖性细胞黏附。用冈田酸抑制 PP2A 或过表达显性失活的 PP2A 使细胞抵抗白藜芦醇对基础或 IGF-1 刺激的磷酸化-Erk1/2 和细胞黏附的抑制作用，而表达野生型 PP2A 则增强了白藜芦醇的抑制作用。过表达野生型 PTEN 或显性失活 Akt 或用 Akt 抑制剂 X 抑制 Akt 增强了白藜芦醇对基础或 IGF-1 刺激的 Erk1/2 磷酸化和细胞黏附的抑制作用。此外，用雷帕霉素抑制机制/哺乳动物雷帕霉素靶蛋白（mTOR）或沉默 mTOR 增强了白藜芦醇对基础和 IGF-1 诱导的 PP2A-PTEN、Akt-Erk1/2 激活和细胞黏附的抑制作用。结果表明，白藜芦醇通过激活 PP2A-PTEN 信号网络抑制 Erk1/2 介导的癌细胞黏附。我们的数据表明，白藜芦醇在预防癌细胞黏附中具有巨大的潜力。
