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The metabolic function of cyclin D3–CDK6 kinase in cancer cell survival
- Source :
- Nature. 546:426-430
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results. Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumour cells reduces flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increases the levels of reactive oxygen species and causes apoptosis of tumour cells. The pro-survival function of cyclin D-associated kinase operates in tumours expressing high levels of cyclin D3-CDK6 complexes. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumour subsets that undergo cell death and tumour regression upon inhibition of CDK4 and CDK6. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism, represents a particularly powerful oncoprotein that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.
- Subjects :
- 0301 basic medicine
Cell Survival
Phosphofructokinase-1
Cyclin D
Pyruvate Kinase
Cyclin A
Cyclin B
Aminopyridines
Apoptosis
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Article
Pentose Phosphate Pathway
Mice
03 medical and health sciences
Cyclin-dependent kinase
Cell Line, Tumor
Neoplasms
Serine
Animals
Humans
Cyclin D3
Phosphorylation
Cyclin-dependent kinase 1
Multidisciplinary
biology
Cell Cycle
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Reactive Nitrogen Species
Xenograft Model Antitumor Assays
Cell biology
Oxidative Stress
030104 developmental biology
Purines
biology.protein
Cyclin-dependent kinase complex
Female
Reactive Oxygen Species
Glycolysis
Cell Division
Cyclin A2
Subjects
Details
- ISSN :
- 14764687 and 00280836
- Volume :
- 546
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....bffbc250125f689cd6fe5d16d2a9221a