Impact of roscovitine, a selective CDK inhibitor, on cancer cells: bi-functionality increases its therapeutic potential

• Autorzy: Wesierska-Gadek J. , Brzoza A. , Komina O. , Maurer M.
• Języki publikacji: EN

Abstrakty

EN

 Increased expression and activity of proteins driving cell cycle progression as well as inactivation of endogenous inhibitors of cyclin-dependent kinases (CDKs) enhance the proliferative potential of cells. Escape of cells during malignant transformation from the proper cell cycle control rendering them independent from growth factors provides rationale for therapeutic targeting of CDKs. Exposure of rapidly growing human MCF-7 breast cancer and HeLa cervix cancer cells to roscovitine (ROSC), a selective inhibitor of CDKs, inhibits their proliferation by induction of cell cycle arrest and/or apoptosis. The outcome strongly depends on the intrinsic traits of the tumor cells, on their cell cycle status prior to the onset of treatment and also on ROSC concentration. At lower dose ROSC primarily inhibits the cell cycle-related CDKs resulting in a strong cell cycle arrest. Interestingly, ROSC arrests asynchronously growing cells at the G2/M transition irrespective of the status of their restriction checkpoint. However, the exposure of cancer cells synchronized after serum starvation in the late G1 phase results in a transient G1 arrest only in cells displaying the intact G1/S checkpoint. At higher dosage ROSC triggers apoptosis. In HeLa cells inhibition of the activity of CDK7 and, in consequence, that of RNA polymerase II is a major event that facilitates the initiation of caspase-dependent apoptosis. In contrast, in the caspase-3-deficient MCF-7 breast cancer cells ROSC induces apoptosis by a p53-dependent pathway. HIPK2-mediated activation of the p53 transcription factor by phosphorylation at Ser46 results in upregulation of p53AIP1 protein. This protein after de novo synthesis and translocation into the mitochondria promotes depolarization of the mitochondrial membrane.

Słowa kluczowe

PL

apoptosis; cell cycle; cyclin-dependent kinase; inhibitor; roscovitine; cancer cell; therapeutic potential

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2009
• Tom: 56
• Numer: 3
• Opis fizyczny: p.495-501,fig.,ref.

Twórcy

autor

Wesierska-Gadek J.

• Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria

autor

Brzoza A.

autor

Komina O.

autor

Maurer M.

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