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CDK8 Kinase Activity Promotes Glycolysis.
Matthew D Galbraith1, Zdenek Andrysik1, Ahwan Pandey1
1Linda Crnic Institute for Down Syndrome, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Cell Reports
|November 9, 2017
Summary
CDK8 kinase activity drives aerobic glycolysis, a key feature of cancer. Inhibiting CDK8 reduces cancer cell growth and sensitizes them to glycolysis inhibitors, suggesting CDK8 as a therapeutic target.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Aerobic glycolysis, or the Warburg effect, is a critical metabolic reprogramming in cancer.
- The precise mechanisms governing this metabolic shift remain incompletely understood.
Purpose of the Study:
- To investigate the role of Mediator-associated kinase CDK8 in regulating aerobic glycolysis in colorectal cancer.
- To determine if CDK8 inhibition impacts cancer cell proliferation and sensitivity to glycolysis inhibitors.
Main Methods:
- Engineered colorectal cancer cells with a point mutation in CDK8.
- Performed transcriptome analysis to assess gene expression changes.
- Assessed glucose uptake, glycolytic capacity, cell proliferation, and anchorage-independent growth.
- Utilized Senexin A, a dual inhibitor of CDK8/CDK19.
Main Results:
- CDK8 kinase activity is essential for the expression of numerous glycolytic pathway components.
- CDK8 inhibition decreased glucose transporter expression, glucose uptake, and overall glycolytic function.
- Impaired CDK8 function reduced cancer cell proliferation and anchorage-independent growth under both normoxia and hypoxia.
- CDK8 inhibition sensitized cancer cells to pharmacological glycolysis inhibition.
Conclusions:
- CDK8 acts as an oncogene by promoting aerobic glycolysis in colorectal cancer.
- Targeting CDK8 warrants further investigation as a therapeutic strategy for highly glycolytic tumors.
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