IRE1α-XBP1s axis regulates SREBP1-dependent MRP1 expression to promote chemoresistance in non-small cell lung cancer cells

被引:1
作者
Xu, Yuzhou [1 ,2 ]
Gui, Feng [1 ,3 ]
Zhang, Zhe [1 ,2 ]
Chen, Zhongyang [1 ,3 ,4 ]
Zhang, Tiange [1 ,5 ]
Hu, Yunhan [1 ,5 ,6 ]
Wei, Huijun [1 ,5 ]
Fu, Yuchen [7 ]
Chen, Xinde [1 ,5 ,6 ]
Wu, Zhihao [1 ,4 ,5 ,8 ]
机构
[1] Wannan Med Coll, Res Lab Tumor Microenvironm, Wuhu 241001, Peoples R China
[2] Wannan Med Coll, Sch Clin Med, Wuhu, Peoples R China
[3] Wannan Med Coll, Sch Stomatol, Wuhu, Peoples R China
[4] Wannan Med Coll, Anhui Prov Engn Res Ctr Dent Mat & Applicat, Wuhu, Peoples R China
[5] Wannan Med Coll, Anhui Prov Key Lab Basic Res & Transformat Age rel, Wuhu, Peoples R China
[6] Wannan Med Coll, Prov Engn Lab Screening & Reevaluat Act Cpds Herba, Wuhu, Peoples R China
[7] Wannan Med Coll, Sch Med Imageol, Wuhu 241001, Peoples R China
[8] Wannan Med Coll, Anhui Prov Key Lab Noncoding RNA Basic & Clin Tran, Wuhu, Peoples R China
基金
中国国家自然科学基金;
关键词
chemoresistance; IRE1; alpha; MRP1; SREBP1; XBP1; LATEST EVIDENCE;
D O I
10.1111/1759-7714.15442
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Inositol-requiring enzyme 1 (IRE1) is an endoplasmic reticulum (ER)-resident transmembrane protein that senses ER stress and mediates an essential arm of the unfolded protein response (UPR). IRE1 reduces ER stress by upregulating the expression of multiple ER chaperones through activation of X-box-binding protein 1 (XBP1). Emerging lines of evidence have revealed that IRE1-XBP1 axis serves as a multipurpose signal transducer during oncogenic transformation and cancer development. In this study, we explore how IRE1-XBP1 signaling promotes chemoresistance in lung cancer. Methods: The expression patterns of UPR components and MRP1 were examined by Western blot. qRT-PCR was employed to determine RNA expression. The promoter activity was determined by luciferase reporter assay. Chemoresistant cancer cells were analyzed by viability, apoptosis. CUT & Tag (Cleavage under targets and tagmentation)-qPCR analysis was used for analysis of DNA-protein interaction. Results: Here we show that activation of IRE1 alpha-XBP1 pathway leads to an increase in MDR-related protein 1 (MRP1) expression, which facilitates drug extrusion and confers resistance to cytotoxic chemotherapy. At the molecular level, XBP1-induced c-Myc is necessary for SREBP1 expression, and SREBP1 binds to the MRP1 promoter to directly regulate its transcription. Conclusions: We conclude that IRE1 alpha-XBP1 had important role in chemoresistance and appears to be a novel prognostic marker for lung cancer.
引用
收藏
页码:2116 / 2127
页数:12
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