CDK11 Loss Induces Cell Cycle Dysfunction and Death of BRAF and NRAS Melanoma Cells.

Rehana L Ahmed,Daniel P Shaughnessy,Janeen H Trembley,Betsy T Kren,Todd P Knutson,Khalil Ahmed,Rachel I Vogel

doi:10.3390/ph12020050

Abstract

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.

Highlights

Melanoma is the fifth most common cancer in the U.S.A., and it is the only common cancer with rapidly increasing rates and little evidence of a reversal of this trend in the foreseeable future [1,2]
Cyclin dependent kinase 11 (CDK11) mRNA levels were lower in malignant cells compared to primary melanocytes in all of the melanoma cell lines tested, except for CDK11A mRNA in WM39 cells
Using a siRNA sequence previously validated for both CDK11 gene transcripts in other cancer types, we evaluated the effects of CDK11 down-regulation on melanoma cell viability [10,34]

Summary

Introduction

Melanoma is the fifth most common cancer in the U.S.A., and it is the only common cancer with rapidly increasing rates and little evidence of a reversal of this trend in the foreseeable future [1,2]. Surgery and chemotherapies continue to be the main strategies in the treatment of melanoma. There are significant side-effects from both traditional chemotherapies as well as newer therapies that target specific proteins and mutations (e.g., BRAF inhibitors). Therapies targeted to specific molecules as well as immune checkpoint blocking drugs have improved survival for melanoma. These therapies are not effective in all melanomas and cure rates for advanced disease remain low [3], in part because melanomas are able to develop resistance to these therapies [4,5]. Only 15% of people with metastatic melanoma survive three years after diagnosis [3]

Methods

Results

Conclusion