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微管动力学是VHL基因缺陷型肾细胞癌的一个治疗靶点。

Microtubule dynamics is a therapeutic vulnerability in VHL-deficient renal cell carcinoma.

作者信息

Pu Yue, Wang Ziruoyu, Tao Shishi, Yang Eun Ju, Wu Songlin, Ren Guowen, Chen Li-Jie, Zhang Xiumei, Tan Kaeling, Dang Yongjun, Shim Joong Sup

机构信息

Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.

Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, China.

出版信息

Int J Biol Sci. 2025 Apr 28;21(7):3286-3305. doi: 10.7150/ijbs.109642. eCollection 2025.

DOI:10.7150/ijbs.109642
PMID:40384876
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12080383/
Abstract

Von Hippel-Lindau (VHL) is a tumor suppressor frequently mutated in renal cell carcinoma (RCC) and its loss has been considered as a target for therapeutic exploitation. In an effort to identify therapeutic vulnerabilities in VHL-deficient RCC, we found that SKPin C1, a SKP2 inhibitor, exhibited synthetic lethal effects on VHL-deficient RCC cells. SKPin C1 selectively disrupted spindle assembly in VHL-deficient RCC, leading to the induction of mitotic arrest and death. These effects were independent of its inhibitory action on SKP2. Our in-depth biochemical and molecular interaction studies reveal that SKPin C1 binds to tubulin and inhibits microtubule polymerization. Interestingly, anti-microtubule effect of SKPin C1 was much more pronounced in VHL-deficient RCC cells. Further mechanistic studies on the synthetic lethality reveal that VHL loss alters microtubule dynamics in cells, promoting microtubule growth speed while reducing stability. Treatment of VHL-deficient RCC cells with SKPin C1 or other microtubule destabilizers strongly suppressed microtubule growth and reduced the levels of GTP-tubulin and acetylated microtubules, resulting in selective vulnerability in VHL-deficient RCC. Taken together, our study suggests that microtubule dynamics is a therapeutic vulnerability in VHL-deficient RCC and provides a rationale for the combination treatment of VHL-deficient RCC with anti-microtubule agents and RCC targeted therapies.

摘要

冯·希佩尔-林道（VHL）是一种在肾细胞癌（RCC）中经常发生突变的肿瘤抑制基因，其缺失被认为是一个可用于治疗的靶点。为了确定VHL缺陷型RCC中的治疗脆弱性，我们发现SKP2抑制剂SKPin C1对VHL缺陷型RCC细胞具有合成致死作用。SKPin C1选择性地破坏VHL缺陷型RCC中的纺锤体组装，导致有丝分裂停滞和细胞死亡。这些作用与其对SKP2的抑制作用无关。我们深入的生化和分子相互作用研究表明，SKPin C1与微管蛋白结合并抑制微管聚合。有趣的是，SKPin C1的抗微管作用在VHL缺陷型RCC细胞中更为明显。对合成致死性的进一步机制研究表明，VHL缺失改变了细胞中的微管动力学，提高了微管生长速度，同时降低了稳定性。用SKPin C1或其他微管破坏剂处理VHL缺陷型RCC细胞可强烈抑制微管生长，并降低GTP-微管蛋白和乙酰化微管的水平，从而导致VHL缺陷型RCC具有选择性脆弱性。综上所述，我们的研究表明微管动力学是VHL缺陷型RCC中的一个治疗脆弱点，并为用抗微管药物和RCC靶向疗法联合治疗VHL缺陷型RCC提供了理论依据。

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本文引用的文献

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VHL-HIF-2α axis-induced SEMA6A upregulation stabilized β-catenin to drive clear cell renal cell carcinoma progression.VHL-HIF-2α 轴诱导 SEMA6A 上调稳定 β-连环蛋白以驱动透明细胞肾细胞癌进展。
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MK-6482 as a potential treatment for von Hippel-Lindau disease-associated clear cell renal cell carcinoma.MK-6482作为治疗与希佩尔-林道病相关的透明细胞肾细胞癌的潜在疗法。
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