Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China.
Laboratory for Biological Medicine, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, P.R. China.
Mol Med Rep. 2018 Jul;18(1):1206-1210. doi: 10.3892/mmr.2018.9038. Epub 2018 May 17.
The majority of molecular targets of anticancer agents are limited to a subset of patients, and therefore identification of more specific biomarkers that can be used to improve clinical outcomes is of increasing interest. The present study showed that von Hippel‑Lindau tumor suppressor (VHL) tumor‑suppressor activity may influence the therapeutic response to Aurora kinase A (AURKA) inhibitors in human renal cell carcinoma (RCC). VHL protein (pVHL) expression was evaluated by immunoblotting in the human RCC cell lines CAKI, ACHN, 786‑O, 769‑P and A498. The anti‑tumor activities of alisertib, an AURKA‑specific chemical inhibitor, were detected by Cell Counting Kit‑8 assay in vitro and mouse xenograft model in vivo. Additionally, the VHL‑mediated anti‑tumor activity was assessed in 769‑P and CAKI cells via the loss or gain of VHL. The results revealed that VHL‑deficient 786‑O, 769‑P and A498 cells were sensitive to alisertib. By contrast, alisertib‑resistant CAKI and ACHN cells expressed the wild type VHL gene. In addition, rescue or knockdown of VHL was observed to increase or decrease alisertib anti‑proliferation activity, respectively, in RCC cells. The inverse correlation between the VHL gene expression profile and alisertib sensitivity was further confirmed in human cancer xenografts models. Taken together, these results suggested that VHL loss could potentially serve as a biomarker for predicting the efficacy of AURKA inhibitors.
大多数抗癌药物的分子靶点仅限于一部分患者，因此，寻找更特异的生物标志物来改善临床结局的兴趣日益增加。本研究表明，von Hippel-Lindau 肿瘤抑制因子（VHL）的肿瘤抑制活性可能影响人肾细胞癌（RCC）中 Aurora 激酶 A（AURKA）抑制剂的治疗反应。通过免疫印迹法评估了人 RCC 细胞系 CAKI、ACHN、786-O、769-P 和 A498 中的 VHL 蛋白（pVHL）表达。通过细胞计数试剂盒-8 法在体外和小鼠异种移植模型中检测了 Aurora 激酶 A 特异性化学抑制剂alisertib 的抗肿瘤活性。此外，通过 VHL 的缺失或获得，评估了 769-P 和 CAKI 细胞中 VHL 介导的抗肿瘤活性。结果表明，VHL 缺失的 786-O、769-P 和 A498 细胞对 alisertib 敏感。相比之下，alisertib 耐药的 CAKI 和 ACHN 细胞表达野生型 VHL 基因。此外，在 RCC 细胞中观察到 VHL 的挽救或敲低分别增加或降低了 alisertib 的抗增殖活性。VHL 基因表达谱与 alisertib 敏感性之间的负相关性在人癌症异种移植模型中得到了进一步证实。综上所述，这些结果表明 VHL 缺失可能可作为预测 AURKA 抑制剂疗效的生物标志物。
