VANGL2 downregulates HINT1 to inhibit the ATM-p53 pathway and promote cisplatin resistance in small cell lung cancer.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-04-08 DOI:10.1038/s41420-025-02424-w

Jiayi Xie, Huiying Liu, Chunqian Yang, Weitao Shen, Jian Zhang

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Abstract

Cisplatin is a first-line drug for the treatment of small cell lung cancer (SCLC). Although the majority of patients with SCLC initially respond to cisplatin therapy, cisplatin resistance readily develops, leading to tumor progression. Therefore, this study aims to elucidate the mechanisms underlying cisplatin resistance in SCLC. We found that VANGL2 is a poor prognostic factor and promotes cisplatin resistance in SCLC. Mechanistically, in cisplatin-resistant cells, VANGL2 overexpression leads to the autophagic degradation of HINT1. This reduction in HINT1 expression further reduces the phosphorylation of ATM and p53 induced by cisplatin-mediated DNA damage. The decreased phosphorylation of p53 inhibits downstream apoptotic pathways, thereby reducing cisplatin-induced apoptosis. In conclusion, VANGL2 regulates the ATM-p53 pathway-mediated apoptotic response of SCLC to cisplatin by downregulating HINT1, thereby promoting cisplatin resistance. Thus, VANGL2 may serve as a potential therapeutic target for reversing cisplatin resistance in SCLC patients.

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.