E3 ligase Skp2-mediated stabilization of survivin contributes to radioresistance.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-04-07 DOI:10.1038/s41420-025-02463-3

Shiming Tan, Ruirui Wang, Jinglin Fang, Ming Yi, Pengfei Guo, Shuangze Han, Xiaoying Li, Yu Gan, Jinzhuang Liao, Xinfang Yu, Wei Li

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Abstract

Oral squamous cell carcinoma (OSCC) is a frequently occurring neck and head malignancy. Therapies for OSCC are improving, but radiotherapy resistance remains a major clinical challenge. Here, we found that the S-phase kinase-associated protein 2 (Skp2) is overexpressed in OSCC cells and tissues. Knockdown of Skp2 significantly increased the radiotherapy sensitivity of OSCC cells. Further potential mechanisms suggest that Skp2-deficient restoration of radiotherapy sensitivity in OSCC cells may induce intrinsic apoptosis through inhibition of the Akt/Wee1/CDK1 axis, which inhibits Survivin phosphorylation and promotes its ubiquitination and degradation by FBXL7. Clinicopathologic histological analysis showed that Skp2 was positively correlated with the expression of p-Akt and Survivin in OSCC tissues. Furthermore, knockdown or inhibition of Skp2 overcame the radiotherapy resistance of OSCC cells. In conclusion, our study demonstrated that targeting the Skp2-Survivin axis could serve as an attractive and promising potential therapeutic target for radiotherapy sensitization in OSCC.

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口腔鳞状细胞癌（OSCC）是一种常见的颈部和头部恶性肿瘤。OSCC的治疗方法正在不断改进，但放疗耐药性仍是一大临床挑战。在这里，我们发现S期激酶相关蛋白2（Skp2）在OSCC细胞和组织中过度表达。敲除Skp2能显著提高OSCC细胞对放疗的敏感性。进一步的潜在机制表明，Skp2缺陷恢复OSCC细胞的放疗敏感性可能是通过抑制Akt/Wee1/CDK1轴，抑制Survivin磷酸化并促进其泛素化和被FBXL7降解，从而诱导内在凋亡。临床病理组织学分析表明，Skp2与OSCC组织中p-Akt和Survivin的表达呈正相关。此外，敲除或抑制Skp2可克服OSCC细胞的放疗耐药性。总之，我们的研究表明，以Skp2-Survivin轴为靶点可作为OSCC放疗增敏的一个有吸引力、有前景的潜在治疗靶点。

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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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.