Doxorubicin induces deglycosylation of cancer cell-intrinsic PD-1 by NGLY1

IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology
Dexuan Wu, Zhen Wu, Han Yao, Xiaojun Yan, Zishan Jiao, Yajing Liu, Meng Zhang, Donglai Wang
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Abstract

Tumor cells can express the immune checkpoint protein programmed death-1 (PD-1), but how cancer cell-intrinsic PD-1 is regulated in response to cellular stresses remains largely unknown. Here, we uncover a unique mechanism by which the chemotherapy drug doxorubicin (Dox) regulates cancer cell-intrinsic PD-1. Dox upregulates PD-1 mRNA while reducing PD-1 protein levels in tumor cells. Although Dox shortens the PD-1 half-life, it fails to directly induce PD-1 degradation. Instead, we observe that Dox promotes the interaction between peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1) and PD-1, facilitating NGLY1-mediated PD-1 deglycosylation and destabilization. The maintenance of PD-1 sensitizes tumor cells to Dox-mediated antiproliferative effects. Our study unveils a regulatory mechanism of PD-1 in response to Dox and highlights a potential role of cancer cell-intrinsic PD-1 in Dox-mediated antitumor effects.

Abstract Image

多柔比星诱导 NGLY1 对癌细胞内源性 PD-1 进行脱糖基化。
肿瘤细胞可以表达免疫检查点蛋白程序性死亡-1(PD-1),但癌细胞内在的 PD-1 是如何在细胞应激反应中受到调控的,目前仍是一个未知数。在这里,我们发现了化疗药物多柔比星(Dox)调节癌细胞内源性 PD-1 的独特机制。Dox 能上调 PD-1 mRNA,同时降低肿瘤细胞中的 PD-1 蛋白水平。虽然 Dox 能缩短 PD-1 的半衰期,但它不能直接诱导 PD-1 降解。相反,我们观察到 Dox 促进了肽-N(4)-(N-乙酰-beta-葡糖胺基)天冬酰胺酰胺酶(NGLY1)和 PD-1 之间的相互作用,促进了 NGLY1 介导的 PD-1 降解和不稳定。PD-1 的维持使肿瘤细胞对 Dox 介导的抗增殖效应敏感。我们的研究揭示了 PD-1 对 Dox 的调控机制,并强调了癌细胞内在 PD-1 在 Dox 介导的抗肿瘤效应中的潜在作用。
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
FEBS Letters
FEBS Letters 生物-生化与分子生物学
CiteScore
7.00
自引率
2.90%
发文量
303
审稿时长
1.0 months
期刊介绍: FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.
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