1. Academic Validation
  2. The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival

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

  • Nature. 2017 Jun 15;546(7658):426-430. doi: 10.1038/nature22797.
Haizhen Wang 1 2 Brandon N Nicolay 3 Joel M Chick 4 Xueliang Gao 1 5 Yan Geng 1 2 Hong Ren 1 2 Hui Gao 6 Guizhi Yang 6 Juliet A Williams 6 Jan M Suski 1 2 Mark A Keibler 7 Ewa Sicinska 8 Ulrike Gerdemann 9 W Nicholas Haining 9 10 11 Thomas M Roberts 1 5 Kornelia Polyak 12 Steven P Gygi 4 Nicholas J Dyson 3 Piotr Sicinski 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
  • 2 Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 3 Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.
  • 4 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 6 Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
  • 7 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 USA.
  • 8 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
  • 9 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
  • 10 Division of Pediatric Hematology and Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
  • 11 Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
  • 12 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
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.

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