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...

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Vydáno v:Nature (London) Ročník 546; číslo 7658; s. 426 - 430
Hlavní autoři: 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 15.06.2017
Nature Publishing Group
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13
ISSN:0028-0836, 1476-4687, 1476-4687
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Abstract 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.
AbstractList D-type cyclins (D1, D2 and D3) and their associated cyclindependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation1,2. Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results2. 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.
D-type cyclins (D1, D2 and D3) together with their associated cyclin-dependent kinases CDK4 and CDK6 are components of the core cell cycle machinery that drives cell proliferation1,2. Inhibitors of CDK4 and CDK6 are currently in clinical trials for patients with several cancer types, with promising results2. Here, we show that cyclin D3-CDK6 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 tumor cells reduces PPP and serine pathway flows, thereby depleting anti-oxidants NADPH and glutathione. This, in turn elevates the levels of reactive oxygen species and causes tumor cell apoptosis. The pro-survival function of cyclin D-associated kinase operates in tumors 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 tumor subsets that undergo cell death and tumor regression upon CDK4/6-inhibition. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism represents a particularly powerful oncogene that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.
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.
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.
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.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.
Author Sicinski, Piotr
Williams, Juliet A.
Gao, Xueliang
Geng, Yan
Ren, Hong
Gao, Hui
Gerdemann, Ulrike
Dyson, Nicholas J.
Wang, Haizhen
Gygi, Steven P.
Chick, Joel M.
Yang, Guizhi
Polyak, Kornelia
Keibler, Mark A.
Sicinska, Ewa
Haining, W. Nicholas
Nicolay, Brandon N.
Suski, Jan M.
Roberts, Thomas M.
AuthorAffiliation 3 Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA
6 Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA
10 Division of Pediatric Hematology and Oncology, Children’s Hospital, Boston, Massachusetts 02115, USA
2 Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
11 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
12 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
8 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
7 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 USA
9 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
1 Department of Cancer Bi
AuthorAffiliation_xml – name: 7 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 USA
– name: 8 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
– name: 11 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
– name: 10 Division of Pediatric Hematology and Oncology, Children’s Hospital, Boston, Massachusetts 02115, USA
– name: 3 Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA
– name: 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
– name: 12 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
– name: 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
– name: 9 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
– name: 2 Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
– name: 6 Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA
– name: 4 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
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  givenname: Haizhen
  surname: Wang
  fullname: Wang, Haizhen
  organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Harvard Medical School
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  organization: Massachusetts General Hospital Cancer Center
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  organization: Department of Cell Biology, Harvard Medical School
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  surname: Geng
  fullname: Geng, Yan
  organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Harvard Medical School
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  surname: Ren
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  organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Harvard Medical School
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  organization: Novartis Institutes for Biomedical Research
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  organization: Novartis Institutes for Biomedical Research
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  surname: Keibler
  fullname: Keibler, Mark A.
  organization: Department of Chemical Engineering, Massachusetts Institute of Technology
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  surname: Sicinska
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  organization: Department of Oncologic Pathology, Dana-Farber Cancer Institute
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  surname: Gerdemann
  fullname: Gerdemann, Ulrike
  organization: Department of Pediatric Oncology, Dana-Farber Cancer Institute
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  givenname: W. Nicholas
  surname: Haining
  fullname: Haining, W. Nicholas
  organization: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Pediatric Hematology and Oncology, Children’s Hospital, Broad Institute of MIT and Harvard
– sequence: 15
  givenname: Thomas M.
  surname: Roberts
  fullname: Roberts, Thomas M.
  organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
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  givenname: Kornelia
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/28607489$$D View this record in MEDLINE/PubMed
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SSID ssj0005174
Score 2.642881
Snippet 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...
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...
D-type cyclins (D1, D2 and D3) and their associated cyclindependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell...
D-type cyclins (D1, D2 and D3) together with their associated cyclin-dependent kinases CDK4 and CDK6 are components of the core cell cycle machinery that...
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pubmed
crossref
springer
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Publisher
StartPage 426
SubjectTerms 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
Title The metabolic function of cyclin D3–CDK6 kinase in cancer cell survival
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https://pubmed.ncbi.nlm.nih.gov/PMC5516959
Volume 546
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