去泛素化酶 USP28 抑制剂 AZ1 单独或与顺铂联合治疗非小细胞肺癌。

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yiqiong Song, Longhao Wang, Yuanyuan Zheng, Lanqi Jia, Chunwei Li, Ke Chao, Lifeng Li, Shilong Sun, Yujie Wei, Yahao Ge, Yaqi Yang, Lili Zhu, Yixing Zhang, Jie Zhao
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引用次数: 0

摘要

肺癌是最常见的恶性肿瘤之一。尽管经过几十年的研究,肺癌的治疗仍然充满挑战。非小细胞肺癌(NSCLC)是肺癌的主要类型,也是肺癌治疗研究的重点。去泛素化酶泛素特异性蛋白酶 28(USP28)在各种肿瘤的进展过程中发挥着作用,是潜在的治疗靶点。本研究旨在确定 USP28 在 NSCLC 进展中的作用。我们研究了 USP28 抑制剂 AZ1 对非小细胞肺癌细胞周期、细胞凋亡、DNA 损伤反应和细胞免疫原性的影响。我们观察到 AZ1 和 siUSP28 会诱导 DNA 损伤,从而激活 Noxa 介导的线粒体凋亡。DNA 损伤和线粒体凋亡释放的 dsDNA 和 mtDNA 通过 cGAS-STING 信号通路激活肿瘤细胞的免疫原性。同时,靶向 USP28 会促进 c-MYC 的降解,导致细胞周期停滞并抑制 DNA 修复。这进一步促进了由 Noxa 蛋白介导的 DNA 损伤诱导的细胞凋亡,从而增强了由 dsDNA 和 mtDNA 介导的肿瘤细胞免疫原性。此外,我们还发现 AZ1 与顺铂(DDP)联用可提高疗效,从而为克服 NSCLC 的顺铂耐药性提供了一种新策略。这些发现表明,靶向 USP28 并将其与顺铂结合是治疗 NSCLC 的可行策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Deubiquitinating enzyme USP28 inhibitor AZ1 alone and in combination with cisplatin for the treatment of non-small cell lung cancer

Deubiquitinating enzyme USP28 inhibitor AZ1 alone and in combination with cisplatin for the treatment of non-small cell lung cancer

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.

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来源期刊
Apoptosis
Apoptosis 生物-生化与分子生物学
CiteScore
9.10
自引率
4.20%
发文量
85
审稿时长
1 months
期刊介绍: Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.
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