Caveolin-1 Promotes Chemoresistance of Gastric Cancer Cells to Cisplatin by Activating WNT/β-Catenin Pathway
Caveolin-1 Promotes Chemoresistance of Gastric Cancer Cells to Cisplatin by Activating WNT/β-Catenin Pathway
复制标题
Caveolin-1通过激活WNT/β-Catenin途径促进胃癌细胞对顺铂的化疗耐药
DOI：
10.3389/fonc.2020.00046
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发表时间：
2020-02-03
影响因子：
4.7
通讯作者：
Fu, Li
中科院分区：
文献类型：
--
作者：
Wang, Xi;Lu, Bin;Fu, Li
耐药性是胃癌（GC）化疗面临的重大挑战，因为胃癌化疗耐药的潜在分子机制仍不明确。窖蛋白 - 1（Cav - 1）是质膜小窝的一种支架蛋白，通过与多种细胞信号相互作用发挥肿瘤调节作用。在本研究中，我们发现，在有Cav - 1存在的情况下，胃癌细胞对顺铂（CDDP）的存活率提高。此外，Cav - 1过表达抑制顺铂诱导的细胞凋亡，并提高了胃癌细胞的存活率。Cav - 1过表达和基因敲低实验表明，Cav - 1的表达通过LRP6的磷酸化和β - 连环蛋白的去磷酸化刺激无翅型MMTV整合位点（WNTs）信号通路。Cav - 1与WNT下游靶基因Met的增加呈正相关，这导致HER2信号的激活。此外，我们的结果表明，Cav - 1和Met的表达与胃癌细胞对顺铂的耐药性呈正相关。综上所述，Cav - 1通过激活WNT信号通路以及Met - HER2的相互作用增强胃癌细胞对顺铂的耐药性。了解Cav - 1在胃癌化疗耐药中的作用，将有助于开发新的治疗方法，以改善胃癌患者的治疗效果。
Drug resistance is a major challenge for chemotherapy in treating human gastric cancer (GC), as the underlying molecular mechanism of chemoresistance in GC remains unknown. Caveolin-1 (Cav-1) is a scaffold protein of plasma membrane caveolae that acts as a tumor modulator by interacting with several cell signals. In this research, we showed that the survival rate of GC cells to cisplatin (CDDP) increased in the presence of Cav-1. Moreover, Cav-1 overexpression inhibited cisplatin-induced apoptosis and improved the survival rate of GC cells. Cav-1 overexpression and knock-down experiments indicated that Cav-1 expression stimulated wingless-type MMTV integration site (WNTs) pathway through the phosphorylation of LRP6 and dephosphorylation of beta-catenin. Cav-1 was positively associated with the increase of WNT downstream target gene Met, which led to the activation of HER2 signaling. Moreover, our results demonstrated that the expression of Cav-1 and Met were positively associated with the resistance of GC cells to cisplatin. Collectively, Cav-1 enhances the cisplatin-resistance of GC cells by activating the WNT signaling pathway and Met-HER2 crosstalk. Understanding the role of Cav-1 in the chemoresistance of GC would help to develop novel therapies for a better treatment outcome of GC patients.