Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle.
Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G(1) 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 G(1) 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.
Department of Biochemistry and Molecular Biology, Faculty of Biology (Edifici Nou), University of Barcelona, Av. Diagonal 645, 08028 Barcelona, Spain. Institute of Biomedicine of the Universitat de Barcelona (IBUB) and CSIC Associated Unit, Barcelona, Spain.
Miriam
M
Zanuy
Antonio
A
Ramos-Montoya
Oscar
O
Villacañas
Nuria
N
Canela
Anibal
A
Miranda
Esther
E
Aguilar
Neus
N
Agell
Oriol
O
Bachs
Jaime
J
Rubio-Martinez
Maria Dolors
MD
Pujol
Wai-Nang P
WN
Lee
Silvia
S
Marin
Marta
M
Cascante