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

IF 2.3 3区医学 Q3 ONCOLOGY

Thoracic Cancer Pub Date : 2024-09-08 DOI:10.1111/1759-7714.15442

Yuzhou Xu, Feng Gui, Zhe Zhang, Zhongyang Chen, Tiange Zhang, Yunhan Hu, Huijun Wei, Yuchen Fu, Xinde Chen, Zhihao Wu

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引用次数: 0

Abstract

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 IRE1α-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 IRE1α-XBP1 had important role in chemoresistance and appears to be a novel prognostic marker for lung cancer.

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IRE1α-XBP1s 轴调节 SREBP1 依赖性 MRP1 的表达，从而促进非小细胞肺癌细胞的化疗抗性。

背景：肌醇需要酶 1（IRE1）是一种内质网（ER）驻留跨膜蛋白，可感知ER压力并介导未折叠蛋白反应（UPR）的重要部分。IRE1 通过激活 X-box 结合蛋白 1 (XBP1)，上调多种 ER 合子的表达，从而减轻 ER 压力。新的证据表明，IRE1-XBP1 轴在致癌转化和癌症发展过程中充当着多功能信号转导器的角色。本研究探讨了 IRE1-XBP1 信号如何促进肺癌的化疗耐药性：方法：通过 Western 印迹检测 UPR 成分和 MRP1 的表达模式。荧光素酶报告实验测定启动子活性。化疗耐药癌细胞的存活率和凋亡率进行了分析。CUT & Tag (Cleavage under targets and tagmentation) -qPCR 分析用于分析 DNA 蛋白相互作用：结果：我们在这里发现，IRE1α-XBP1 通路的激活会导致 MDR 相关蛋白 1（MRP1）的表达增加，从而促进药物挤出并产生对细胞毒性化疗的耐药性。在分子水平上，XBP1诱导的c-Myc是SREBP1表达的必要条件，SREBP1与MRP1启动子结合直接调控其转录：我们得出结论：IRE1α-XBP1在化疗耐药性中起着重要作用，似乎是肺癌的一种新型预后标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Thoracic Cancer ONCOLOGY-RESPIRATORY SYSTEM

CiteScore

5.20

自引率

3.40%

发文量

439

审稿时长

2 months

期刊介绍： Thoracic Cancer aims to facilitate international collaboration and exchange of comprehensive and cutting-edge information on basic, translational, and applied clinical research in lung cancer, esophageal cancer, mediastinal cancer, breast cancer and other thoracic malignancies. Prevention, treatment and research relevant to Asia-Pacific is a focus area, but submissions from all regions are welcomed. The editors encourage contributions relevant to prevention, general thoracic surgery, medical oncology, radiology, radiation medicine, pathology, basic cancer research, as well as epidemiological and translational studies in thoracic cancer. Thoracic Cancer is the official publication of the Chinese Society of Lung Cancer, International Chinese Society of Thoracic Surgery and is endorsed by the Korean Association for the Study of Lung Cancer and the Hong Kong Cancer Therapy Society. The Journal publishes a range of article types including: Editorials, Invited Reviews, Mini Reviews, Original Articles, Clinical Guidelines, Technological Notes, Imaging in thoracic cancer, Meeting Reports, Case Reports, Letters to the Editor, Commentaries, and Brief Reports.