Wang Xi, Lu Bin, Dai Chunyan, Fu Yufei, Hao Ke, Zhao Bing, Chen Zhe, Fu Li
Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
Front Oncol. 2020 Feb 3;10:46. doi: 10.3389/fonc.2020.00046. eCollection 2020.
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 β-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.
耐药性是人类胃癌（GC）化疗面临的一项重大挑战，因为GC中化疗耐药的潜在分子机制仍不清楚。小窝蛋白-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，在存在Cav-1的情况下，GC细胞对顺铂（CDDP）的存活率增加。此外，Cav-1过表达抑制顺铂诱导的细胞凋亡并提高GC细胞的存活率。Cav-1过表达和敲低实验表明，Cav-1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）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GC细胞对顺铂的耐药性呈正相关。总的来说，Cav-1通过激活WNT信号通路和Met-HER2串扰增强GC细胞对顺铂的耐药性。了解Cav-1在GC化疗耐药中的作用将有助于开发新的疗法，以改善GC患者的治疗效果。
