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Title: Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle
Author: Zanuy Porquet, Miriam
Ramos Montoya, Antonio Francisco
Villacañas, Oscar
Canela i Canela, Núria
Miranda, Aníbal
Aguilar Fadó, Esther
Agell i Jané, Neus
Bachs Valldeneu, Oriol
Rubio Martínez, Jaime
Pujol Dilmé, M. Dolors
Lee, Paul Wai Nang
Marín Martínez, Silvia
Cascante i Serratosa, Marta
Keywords: Malalties del còlon
Proteïnes quinases
Colon diseases
Protein kinases
Issue Date: 1-Jun-2012
Publisher: Springer Science + Business Media
Abstract: 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 hall- mark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM 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 (the calcein acetoxymethyl-ester) on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phos-phate pathway was significantly altered. To elucidate whe-ther 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.
Note: Versió postprint del document publicat a:
It is part of: Metabolomics, 2012, vol. 8, num. 3, p. 454-464
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ISSN: 1573-3882
Appears in Collections:Articles publicats en revistes (Biomedicina)

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