A novel ribosomal protein S6 kinase 2 inhibitor attenuates the malignant phenotype of cutaneous malignant melanoma cells by inducing cell cycle arrest and apoptosis

Malignant melanoma (MM) is a highly life-threatening tumor causing the majority of the cutaneous cancer-related deaths. Previously, ribosomal protein S6 kinase 2 (RSK2), the downstream effector of the MAPK pathway, represents a therapeutic target in melanoma. AE007 is discovered as a targeted RSK2 inhibitor, and subsequent results showed that AE007 inhibits RSK2 by directly binding to its protein kinase domain. AE007 causes cell cycle arrest and cellular apoptosis, thereby dramatically inhibiting proliferation, migration, and invasion of melanoma cells. Nevertheless, melanocytes and keratinocytes are not affected by this compound. In addition, suppression of RSK2 abrogates the inhibitory effect of AE007 on melanoma cell proliferation. AE007 treatment significantly inhibits the expression of Cyclin D1, Cyclin B1, CDK2, and Bcl-2, while raises the cleavage of PARP. Moreover, RNA sequencing results show that AE007 treatment can affect the genes expression profile, including the expression of cell cycle and DNA replication genes. In conclusion, AE007 is a promising melanoma therapeutic agent by targeting RSK2.

恶性黑色素瘤（Malignant melanoma, MM）是一类高致死性肿瘤，亦是引发皮肤癌相关死亡的主要病因。既往研究表明，丝裂原活化蛋白激酶（MAPK）通路的下游效应分子核糖体蛋白S6激酶2（ribosomal protein S6 kinase 2, RSK2）可作为黑色素瘤的治疗靶点。研究人员发现AE007是一种靶向RSK2的抑制剂，后续实验结果显示，AE007可通过直接结合RSK2的蛋白激酶结构域来抑制其活性。AE007可诱导细胞周期阻滞与细胞凋亡，从而显著抑制黑色素瘤细胞的增殖、迁移与侵袭能力，但该化合物对黑素细胞与角质形成细胞无影响。此外，抑制RSK2可抵消AE007对黑色素瘤细胞增殖的抑制作用。AE007处理可显著下调细胞周期蛋白D1（Cyclin D1）、细胞周期蛋白B1（Cyclin B1）、细胞周期蛋白依赖性激酶2（CDK2）以及B细胞淋巴瘤-2（Bcl-2）的表达水平，同时上调多聚ADP核糖聚合酶（PARP）的剪切体表达。此外，RNA测序（RNA sequencing）结果显示，AE007处理可改变细胞的基因表达谱，包括细胞周期与DNA复制相关基因的表达变化。综上，AE007是一种极具潜力的靶向RSK2的黑色素瘤治疗候选药物。