CircPDIA3/miR-449a/XBP1反馈环路通过抑制GSDME-C结构域的棕榈酰化来抑制热蛋白沉积,从而诱导结直肠癌的化疗耐药性

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-05-28 DOI:10.1016/j.drup.2024.101097
Jiatong Lin , Zejian Lyu , Huolun Feng , Huajie Xie , Jingwen Peng , Weifu Zhang , Jun Zheng , Jiabin Zheng , Zihao Pan , Yong Li
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引用次数: 0

摘要

尽管奥沙利铂(OXA)被广泛应用于结直肠癌(CRC)的一线治疗,但由于对 OXA 产生耐药性,CRC 复发现象十分常见。OXA 耐药性与多种因素有关,包括热蛋白沉积的异常调控。因此,阐明热蛋白沉积的异常调控机制非常重要。在这里,我们发现环状 RNA circPDIA3 在 CRC 的化疗耐药性中发挥了重要作用。循环RNA circPDIA3可通过抑制体外和体内的热凋亡诱导CRC的化疗耐药性。从机理上讲,RIP、RNA pull-down和co-IP实验发现,circPDIA3直接与GSDME-C结构域结合,然后通过阻断ZDHHC3和ZDHHC17对GSDME-C结构域棕榈酰化,增强GSDME-C结构域的自身抑制作用,从而抑制热凋亡。此外,研究还发现,circPDIA3/miR-449a/XBP1正反馈回路增加了circPDIA3的表达,从而诱导化疗耐药。此外,我们的临床数据和患者来源的肿瘤异种移植(PDX)模型也支持 circPDIA3 与 CRC 患者化疗耐药性的发生呈正相关。综上所述,我们的研究结果表明,circPDIA3可通过抑制GSDME-C结构域棕榈酰化,放大GSDME-C结构域的自身抑制作用,从而促进CRC的化疗耐药性。这项研究为我们揭示circRNA调控化脓过程的机制提供了新的视角,并为逆转CRC的化疗耐药性提供了潜在的治疗靶点。
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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CircPDIA3/miR-449a/XBP1 feedback loop curbs pyroptosis by inhibiting palmitoylation of the GSDME-C domain to induce chemoresistance of colorectal cancer

Although oxaliplatin (OXA) is widely used in the frontline treatment of colorectal cancer (CRC), CRC recurrence is commonly observed due to OXA resistance. OXA resistance is associated with a number of factors, including abnormal regulation of pyroptosis. It is therefore important to elucidate the abnormal regulatory mechanism underlying pyroptosis. Here, we identified that the circular RNA circPDIA3 played an important role in chemoresistance in CRC. CircPDIA3 could induce chemoresistance in CRC by inhibiting pyroptosis both in vitro and in vivo. Mechanistically, RIP, RNA pull-down and co-IP assays revealed that circPDIA3 directly bonded to the GSDME-C domain, subsequently enhanced the autoinhibitory effect of the GSDME-C domain through blocking the GSDME-C domain palmitoylation by ZDHHC3 and ZDHHC17, thereby restraining pyroptosis. Additionally, it was found that the circPDIA3/miR-449a/XBP1 positive feedback loop increased the expression of circPDIA3 to induce chemoresistance. Furthermore, our clinical data and patient-derived tumor xenograft (PDX) models supported the positive association of circPDIA3 with development of chemoresistance in CRC patients. Taken together, our findings demonstrated that circPDIA3 could promote chemoresistance by amplifying the autoinhibitory effect of the GSDME-C domain through inhibition of the GSDME-C domain palmitoylation in CRC. This study provides novel insights into the mechanism of circRNA in regulating pyroptosis and providing a potential therapeutic target for reversing chemoresistance of CRC.

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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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