Ahmed Rehana L, Shaughnessy Daniel P, Knutson Todd P, Vogel Rachel I, Ahmed Khalil, Kren Betsy T, Trembley Janeen H
Department of Dermatology, University of Minnesota, Minneapolis, MN 55455, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Pharmaceuticals (Basel). 2019 Apr 2;12(2):50. doi: 10.3390/ph12020050.
Cyclin dependent kinase 11 (CDK11) is a protein kinase that regulates RNA transcription, pre-mRNA splicing, mitosis, and cell death. Targeting of CDK11 expression levels is effective in the experimental treatment of breast and other cancers, but these data are lacking in melanoma. To understand CDK11 function in melanoma, we evaluated protein and RNA levels of CDK11, Cyclin L1 and Cyclin L2 in benign melanocytes and BRAF- as well as NRAS-mutant melanoma cell lines. We investigated the effectiveness of reducing expression of this survival kinase using RNA interference on viability, clonal survival, and tumorsphere formation in melanoma cell lines. We examined the impact of CDK11 loss in BRAF-mutant melanoma on more than 700 genes important in cancer signaling pathways. Follow-up analysis evaluated how CDK11 loss alters cell cycle function in BRAF- and NRAS-mutant melanoma cells. We present data on CDK11, CCNL1 and CCNL2 mRNA expression in melanoma patients, including prognosis for survival. In sum, we found that CDK11 is necessary for melanoma cell survival, and a major impact of CDK11 loss in melanoma is to cause disruption of the cell cycle distribution with accumulation of G1- and loss of G2/M-phase cancer cells.
细胞周期蛋白依赖性激酶11（CDK11）是一种蛋白激酶，可调节RNA转录、前体mRNA剪接、有丝分裂和细胞死亡。靶向CDK11表达水平在乳腺癌和其他癌症的实验性治疗中有效，但黑色素瘤缺乏这些数据。为了解CDK11在黑色素瘤中的功能，我们评估了良性黑素细胞以及BRAF和NRAS突变的黑色素瘤细胞系中CDK11、细胞周期蛋白L1和细胞周期蛋白L2的蛋白质和RNA水平。我们研究了使用RNA干扰降低这种存活激酶的表达对黑色素瘤细胞系的活力、克隆存活和肿瘤球形成的有效性。我们研究了BRAF突变的黑色素瘤中CDK11缺失对癌症信号通路中700多个重要基因的影响。后续分析评估了CDK11缺失如何改变BRAF和NRAS突变的黑色素瘤细胞中的细胞周期功能。我们展示了黑色素瘤患者中CDK11、CCNL1和CCNL2 mRNA表达的数据，包括生存预后。总之，我们发现CDK11是黑色素瘤细胞存活所必需的，黑色素瘤中CDK11缺失的主要影响是导致细胞周期分布紊乱，G1期细胞积累，G2/M期癌细胞丢失。
