The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival.

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.

• Authors: Haizhen Wang, Brandon N Nicolay, Joel M Chick, Xueliang Gao, Yan Geng, Hong Ren, Hui Gao, Guizhi Yang, Juliet A Williams, Jan M Suski, Mark A Keibler, Ewa Sicinska, Ulrike Gerdemann, W Nicholas Haining, Thomas M Roberts, Kornelia Polyak, Steven P Gygi, Nicholas J Dyson, Piotr Sicinski
• Journal: Nature (Nature) Vol. 546 Issue 7658 Pg. 426-430 (06 15 2017) ISSN: 1476-4687 [Electronic] England
• PMID: 28607489 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Cyclin D3
• Purines
• Reactive Nitrogen Species
• Reactive Oxygen Species
• Serine
• Phosphofructokinase-1
• Pyruvate Kinase
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• ribociclib

Topics

• Aminopyridines (pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclin D3 (metabolism)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors, metabolism)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors, metabolism)
• Female
• Glycolysis (drug effects)
• Humans
• Mice
• Neoplasms (drug therapy, enzymology, metabolism, pathology)
• Oxidative Stress (drug effects)
• Pentose Phosphate Pathway (drug effects)
• Phosphofructokinase-1 (metabolism)
• Phosphorylation (drug effects)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (enzymology, metabolism, pathology)
• Purines (pharmacology, therapeutic use)
• Pyruvate Kinase (metabolism)
• Reactive Nitrogen Species (metabolism)
• Reactive Oxygen Species (metabolism)
• Serine (metabolism)
• Xenograft Model Antitumor Assays