Fas signaling promotes chemoresistance in gastrointestinal cancer by up-regulating P-glycoprotein

Abstract

// Haoxuan Zheng 1, * , Zhizhong Liu 1, 2, * , Tao Liu 1, * , Yidong Cai 1, 3, * , Yadong Wang 1 , Shiyong Lin 1, 4 , Jinmin Chen 1 , Jing Wang 1 , Zhiqing Wang 1 , Bo Jiang 1 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China 2 Department of Gastroenterology, the Second People’s Hospital of Zhuhai, Zhuhai 519020, China 3 Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China 4 Department of Endoscopy and Laser, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China * These authors contributed equally to this work Correspondence to: Haoxuan Zheng, e-mail: haoxuan.zheng@gmail.com Keywords: Fas signaling, epithelial-mesenchymal transition, chemoresistance, gastrointestinal cancer Received: July 09, 2014      Accepted: September 16, 2014      Published: October 15, 2014 ABSTRACT Fas signaling promotes metastasis of gastrointestinal (GI) cancer cells by inducing epithelial-mesenchymal transition (EMT), and EMT acquisition has been found to cause cancer chemoresistance. Here, we demonstrated that the response to chemotherapy of GI cancer patients with higher expression of FasL was significantly worse than patients with lower expression. Fas-induced activation of the ERK1/2-MAPK pathway decreased the sensitivity of GI cancer cells to chemotherapeutic agents and promoted the expression of P-glycoprotein (P-gp). FasL promoted chemoresistance of GI cancer cell via upregulation of P-gp by increasing β-catenin and decreasing miR-145. β-catenin promoted P-gp gene transcription by binding with P-gp promoter while miR-145 suppressed P-gp expression by interacting with the mRNA 3’UTR of P-gp. Immunostaining and qRT-PCR analysis of human GI cancer samples revealed a positive association among FasL, β-catenin, and P-gp, but a negative correlation between miR-145 and FasL or P-gp. Altogether, our results showed Fas signaling could promote chemoresistance in GI cancer through modulation of P-gp expression by β-catenin and miR-145. Our findings suggest that Fas signaling-based cancer therapies should be administered cautiously, as activation of this pathway may not only lead to apoptosis but also induce chemoresistance.