Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China.
Br J Cancer. 2024 Aug;131(3):444-456. doi: 10.1038/s41416-024-02750-3. Epub 2024 Jun 18.
The combined use of CDK4/6 inhibitors and mTOR inhibitors has achieved some clinical success in ccRCC. Exploring the underlying mechanism of the CDK4/6 pathway in cancer cells and the drug interactions of CDK4/6 inhibitors in combination therapy could help identify new therapeutic strategies for ccRCC. Notably, CDK4/6 inhibitors inactivate the mTOR pathway by increasing the protein levels of TSC1, but the mechanism by which CDK4/6 inhibitors regulate TSC1 is still unclear.
Mass spectrometry analysis, coimmunoprecipitation analysis, GST pull-down assays, immunofluorescence assays, Western blot analysis and RT‒qPCR analysis were applied to explore the relationships among CDK4, RNF26 and TSC1. Transwell assays, tube formation assays, CCK-8 assays, colony formation assays and xenograft assays were performed to examine the biological role of RNF26 in renal cancer cells.TCGA-KIRC dataset analysis and RT‒qPCR analysis were used to examine the pathways affected by RNF26 silencing.
CDK4/6 inhibitors stabilized TSC1 in cancer cells. We showed that CDK4 enhances the interaction between TSC1 and RNF26 and that RNF26 activates the mTOR signaling pathway in ccRCC, contributes to ccRCC progression and angiogenesis, and promotes tumorigenesis. We then found that RNF26 functions as an E3 ligase of TSC1 to regulate CDK4-induced TSC1. This finding suggested that RNF26 promotes ccRCC progression and angiogenesis to some extent by negatively regulating TSC1.
Our results revealed a novel CDK4/RNF26/TSC1 axis that regulates the anticancer efficacy of CDK4/6 inhibitors and mTOR inhibitors in ccRCC.
CDK4/6 抑制剂与 mTOR 抑制剂联合使用在 ccRCC 中取得了一定的临床疗效。探索癌症细胞中 CDK4/6 通路的潜在机制以及 CDK4/6 抑制剂在联合治疗中的药物相互作用，有助于为 ccRCC 确定新的治疗策略。值得注意的是，CDK4/6 抑制剂通过增加 TSC1 的蛋白水平使 mTOR 通路失活，但 CDK4/6 抑制剂调节 TSC1 的机制尚不清楚。
应用质谱分析、共免疫沉淀分析、GST 下拉实验、免疫荧光分析、Western blot 分析和 RT-qPCR 分析来探索 CDK4、RNF26 和 TSC1 之间的关系。Transwell 实验、管形成实验、CCK-8 实验、集落形成实验和异种移植实验用于研究 RNF26 在肾癌细胞中的生物学作用。TCGA-KIRC 数据集分析和 RT-qPCR 分析用于检测 RNF26 沉默影响的通路。
CDK4/6 抑制剂在癌细胞中稳定 TSC1。我们发现 CDK4 增强了 TSC1 与 RNF26 的相互作用，RNF26 在 ccRCC 中激活 mTOR 信号通路，促进 ccRCC 进展和血管生成，并促进肿瘤发生。我们随后发现 RNF26 作为 TSC1 的 E3 连接酶发挥作用，以调节 CDK4 诱导的 TSC1。这一发现表明，RNF26 在一定程度上通过负向调节 TSC1 来促进 ccRCC 的进展和血管生成。
我们的结果揭示了一个新的 CDK4/RNF26/TSC1 轴，该轴调节了 CDK4/6 抑制剂和 mTOR 抑制剂在 ccRCC 中的抗癌疗效。
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