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

The cyclin D3–CDK6 kinase complex, which is overactive in some cancers, inhibits two key glycolysis enzymes and thereby enhances the levels of antioxidants in cells, promoting tumour cell survival. Cancer cell survival by cyclin D3–CDK6 metabolism Cyclin–CDK complexes are commonly amplified in cance...

Full description

Saved in:

Bibliographic Details
Published in:	Nature (London) Vol. 546; no. 7658; pp. 426 - 430
Main Authors:	Wang, Haizhen, Nicolay, Brandon N., Chick, Joel M., Gao, Xueliang, Geng, Yan, Ren, Hong, Gao, Hui, Yang, Guizhi, Williams, Juliet A., Suski, Jan M., Keibler, Mark A., Sicinska, Ewa, Gerdemann, Ulrike, Haining, W. Nicholas, Roberts, Thomas M., Polyak, Kornelia, Gygi, Steven P., Dyson, Nicholas J., Sicinski, Piotr
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 15.06.2017 Nature Publishing Group
Subjects:	13 13/106 13/2 13/31 6-Phosphofructokinase 631/67/2327 631/80/641 631/80/82 Aminopyridines - pharmacology Aminopyridines - therapeutic use Animals Antioxidants Apoptosis Apoptosis - drug effects Brain cancer Cancer Catalysis Catalytic activity Cell cycle Cell Cycle - drug effects Cell death Cell Line, Tumor Cell survival Cell Survival - drug effects Clinical trials Cyclin D Cyclin D3 Cyclin D3 - metabolism Cyclin-dependent kinase 4 Cyclin-Dependent Kinase 4 - antagonists & inhibitors Cyclin-Dependent Kinase 4 - metabolism Cyclin-dependent kinase 6 Cyclin-Dependent Kinase 6 - antagonists & inhibitors Cyclin-Dependent Kinase 6 - metabolism Cyclin-dependent kinases Enzymes Female Glutathione Glycolysis Glycolysis - drug effects Humanities and Social Sciences Humans Intermediates Kinases letter Machinery and equipment Mass spectrometry Medical research Metabolism Metabolites Mice multidisciplinary NADP Neoplasms - drug therapy Neoplasms - enzymology Neoplasms - metabolism Neoplasms - pathology Oxidative Stress - drug effects Oxygen Pentose Pentose phosphate pathway Pentose Phosphate Pathway - drug effects Phosphofructokinase Phosphofructokinase-1 - metabolism Phosphorylation Phosphorylation - drug effects Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - enzymology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology Proteins Purines - pharmacology Purines - therapeutic use Pyruvate kinase Pyruvate Kinase - metabolism Reactive Nitrogen Species - metabolism Reactive oxygen species Reactive Oxygen Species - metabolism Science Scientific imaging Serine - metabolism Survival Tumors Xenograft Model Antitumor Assays Xenografts
ISSN:	0028-0836, 1476-4687, 1476-4687
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	The cyclin D3–CDK6 kinase complex, which is overactive in some cancers, inhibits two key glycolysis enzymes and thereby enhances the levels of antioxidants in cells, promoting tumour cell survival. Cancer cell survival by cyclin D3–CDK6 metabolism Cyclin–CDK complexes are commonly amplified in cancer and promote cell cycle progression. Inhibitors for CDK4/6 are being tested in clinical trials and are thought to work in patients that retain expression of the CDK substrate RB1. Here, the authors describe an additional pro-survival role of one cyclin–CDK complex, D3–CDK6, which controls cellular metabolism. When hyperactivated in cancer cells, the complex phosphorylates and inactivates two glycolysis enzymes. This redirects glycolytic intermediates to the pentose phosphate and serine pathways, providing enhanced antioxidant capacity. CDK4/6 inhibitors can induce apoptosis by increasing the oxidative stress in tumour cells expressing high levels of D3–CDK6 complexes. The findings suggest that, in addition to RB1, markers such as levels of D3–CDK6 complexes could be useful for identifying patients likely to respond to CDK4/6 inhibitors. 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 1 , 2 . Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results 2 . 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Reprints and requests for materials should be addressed to PS. P.S., T.M.R., K.P. are consultants/recipients of research grants from Novartis, H.G. G.Y., J.A.W. employees of Novartis Institutes for BioMedical Research.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/nature22797