RSK4小分子抑制剂在肾透明细胞癌中的作用研究
Role of RSK4 small-molecule inhibitors in clear cell renal cell carcinoma
马静 1彭阳 1许军鹏 1刘一雄 1范林妮1
作者信息
- 1. 空军军医大学:基础医学院病理学教研室,西京医院病理科,陕西西安 710032
- 折叠
摘要
目的 核糖体S6蛋白激酶4(RSK4)在肾透明细胞癌中高表达,并与预后相关,提示其可能为肾细胞癌(RCC)恶性进展的关键激酶分子之一,并有望作为一个新的潜在的激酶治疗靶点.方法 初步合成并筛选出一个特异性针对RSK4的小分子化合物;利用Western blotting方法检测加药后RSK4及其下游糖原合成酶激酶3β(GSK-3β)、核糖体蛋白S6(rpS6)等底物的活性并筛选出一个抑制作用最强的药物;利用Transwell及CCK-8检测加药后RCC细胞系侵袭迁移及增殖能力的变化.结果 我们前期从表皮生长因子受体抑制剂库中筛选出对RSK4具有强抑制作用的3个小分子并通过改变结构得到5种药物.经过筛选,体外实验发现CZ-54可以特异性抑制RSK4及其下游rpS6、GSK-3β底物的活性,抑制RSK4后可以显著降低肿瘤细胞的增殖及侵袭迁移能力.结论 RSK4在RCC中高表达,而特异性的小分子激酶抑制剂CZ-54可以抑制RSK4及下游分子的表达,从而降低RCC的增殖及侵袭迁移能力,为临床上晚期及难治性RCC的治疗提供了新方向.
Abstract
Objective Ribosomal S6 protein kinase 4(RSK4)is highly expressed in clear cell renal cell carcinoma and is associated with prognosis,suggesting that it may be one of the key kinase molecules in the malignant progression of renal cell carcinoma(RCC)and is expected to be a new potential kinase therapeutic target.Methods A small-molecule compound specific to RSK4 was synthesized and screened.Western blotting method was used to detect the activity of substrates such as RSK4 and its downstream glycogen synthase kinase-3β(GSK-3β)and ribosomal protein S6(rpS6)after dosing,and screen out a drug with the strongest inhibitory effect.Transwell and CCK-8 were used to detect the changes in the invasion,migration and proliferation ability of RCC cell lines after dosing.Results We screened three small molecules with strong inhibitory effect on RSK4 from the epidermal grouth factor receptor inhibitor library in the early stage,and obtained five drugs by changing the structure.After screening,in vitro experiments showed that CZ-54 could specifically inhibit the activity of RSK4 and its downstream substrates rpS6 and GSK-3β,and inhibition of RSK4 could significantly reduce the proliferation,invasion and migration of tumor cells.Conclusion RSK4 is highly expressed in RCC,and the specific small-molecule kinase inhibitor CZ-54 can inhibit the expression of RSK4 and its downstream molecules,thereby reducing the proliferation,invasion and migration ability of RCC,which provides a new direction for the treatment of advanced and refractory RCC in clinical practice.
关键词
肾细胞癌/RSK4/小分子激酶抑制剂/靶向治疗Key words
renal cell carcinoma/RSK4/small-molecule kinase inhibitor/targeted therapy引用本文复制引用
基金项目
国家自然科学基金(82072654)
陕西省自然科学基金青年科学基金(2021JQ-351)
出版年
2024
国家科技期刊平台
NSTL
万方数据