Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle

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• 作者：Miriam Zanuy (1) (2)
  Antonio Ramos-Montoya (1) (2) (7)
  Oscar Villaca?as (3) (8)
  Nuria Canela (4)
  Anibal Miranda (1) (2)
  Esther Aguilar (1) (2)
  Neus Agell (4)
  Oriol Bachs (4)
  Jaime Rubio-Martinez (3)
  Maria Dolors Pujol (5)
  Wai-Nang P. Lee (6)
  Silvia Marin (1) (2)
  Marta Cascante (1) (2)
  
• 关键词：Cyclin ; dependent kinases ; CDK ; inhibitor ; Tracer ; based metabolomics ; Pentose phosphate pathway ; Phase ; plane analysis
• 刊名：Metabolomics
• 出版年：2012
• 出版时间：June 2012
• 年：2012
• 卷：8
• 期：3
• 页码：454-464
• 全文大小：381KB
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• 作者单位：Miriam Zanuy (1) (2)
  Antonio Ramos-Montoya (1) (2) (7)
  Oscar Villaca?as (3) (8)
  Nuria Canela (4)
  Anibal Miranda (1) (2)
  Esther Aguilar (1) (2)
  Neus Agell (4)
  Oriol Bachs (4)
  Jaime Rubio-Martinez (3)
  Maria Dolors Pujol (5)
  Wai-Nang P. Lee (6)
  Silvia Marin (1) (2)
  Marta Cascante (1) (2)
  
  1. Department of Biochemistry and Molecular Biology, Faculty of Biology (Edifici Nou), University of Barcelona, Av. Diagonal 645, 08028, Barcelona, Spain
  2. Institute of Biomedicine of the Universitat de Barcelona (IBUB) and CSIC Associated Unit, Barcelona, Spain
  7. Uro-Oncology Research Group, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
  3. Department of Physical Chemistry, Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, Martí i Franqués 1, 08028, Barcelona, Spain
  8. Intelligent Pharma S.L, C/Baldiri Reixac 4, 08028, Barcelona, Spain
  4. Department of Cell Biology, Immunology and Neurosciencies, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Spain
  5. Department of Pharmacology and Therapeutic Chemistry, CSIC Associated Unit, Faculty of Pharmacy, Universitat de Barcelona, Joan XXIII, s/n, 08028, Barcelona, Spain
  6. Department of Pediatrics, Los Angeles Biomedical Research Institute at the Harbor-UCLA Medical Center, RB1, 1124 West Carson Street, Torrance, CA, 90502, USA
  
• ISSN：1573-3890

文摘

Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G1 phase. Aberrant expression of CDK4 and CDK6 is a hallmark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM (the calcein acetoxymethyl-ester) is a potent specific inhibitor of CDK4 and CDK6 in HCT116 human colon adenocarcinoma cells, inhibiting retinoblastoma protein (pRb) phosphorylation and inducing cell cycle arrest in the G1 phase. The metabolic effects of calcein AM on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phosphate pathway was significantly altered. To elucidate whether these metabolic changes were due to the inhibition of CDK4 and CDK6, we also characterized the metabolic profile of a CDK4, CDK6 and CDK2 triple knockout of mouse embryonic fibroblasts. The results show that the metabolic profile associated with the depletion of CDK4, CDK6 and CDK2 coincides with the metabolic changes induced by calcein AM on HCT116 cells, thus confirming that the inhibition of CDK4 and CDK6 disrupts the balance between the oxidative and non-oxidative branches of the pentose phosphate pathway. Taken together, these results indicate that low doses of calcein can halt cell division and kill tumor cells. Thus, selective inhibition of CDK4 and CDK6 may be of greater pharmacological interest, since inhibitors of these kinases affect both cell cycle progression and the robust metabolic profile of tumors.