Targeting autophagy enhances apatinib-induced apoptosis via endoplasmic reticulum stress for human colorectal cancer. (1st September 2018)

• Record Type: Journal Article
• Authors: Cheng, Xi; Feng, Haoran; Wu, Haoxuan; Jin, Zhijian; Shen, Xiaonan; Kuang, Jie; Huo, Zhen; Chen, Xianze; Gao, Haoji; Ye, Feng; Ji, Xiaopin; Jing, Xiaoqian; Zhang, Yaqi; Zhang, Tao; Qiu, Weihua; Zhao, Ren
• Is Part Of: Cancer letters. Volume 431(2018)
• Page Start: 105
• Page End: 114
• Publication Date: 2018-09-01
• Subjects: Tyrosine kinase inhibitor -- Chloroquine -- IRE1α -- Drug resistance; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.05.046
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma and some other solid tumors. However, the direct functional mechanisms of tumor lethality mediated by apatinib have not yet been fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, in this study, we demonstrated that apatinib could induce both apoptosis and autophagy in human colorectal cancer (CRC) via a mechanism that involved endoplasmic reticulum (ER) stress. Moreover, activation of the IRE1α pathway from apatinib-induced ER stress is responsible for the induction of autophagy; however, blocking autophagy could enhance the apoptosis in apatinib-treated human CRC cell lines. Furthermore, the combination of apatinib with autophagy inhibitor chloroquine (CQ) tends to have the most significant anti-tumor effect of CRC both in vitro and in vivo . Overall, our data show that because apatinib treatment could induce ER stress-related apoptosis and protective autophagy in human CRC cell lines, targeting autophagy is a promising therapeutic strategy to relieve apatinib drug resistance in CRC. Highlights: Apatinib could induce both apoptosis and autophagy in CRC via endoplasmic reticulum stress. IRE1α pathway is responsible for Apatinib induced autophagy Apatinib could induce protective autophagy in CRC cells and led to Apatinib drug resistence. Combination of Apatinib with chloroquine have the most significant anti-tumor effect of CRC both in vitro and in vivo . Targeting autophagy is a promising therapeutic strategy to relieve Apatinib drug resistance in CRC.