Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC (Nat Med, 2007, 13:820-827)

報告日期: 2007/09/28
報告時間: 17:10/18:00
報告學生: 侯佳成
講評老師: 洪良宜
附件下載:

Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC

2007 NATURE MEDICINE

Speaker: 侯佳成

Commentator: 洪良宜

Date: 9/28/07

Room: 602

Abstract:

In eukaryotic cells, cyclin-dependent kinase complexes regulate the temporal progression of cells through the cell cycle. Deregulation in the cell cycle is an essential component in the evolution of cancer especially sensitive to the inhibition of cyclin-dependent kinases (CDKs), important regulators of cell cycle progression. In mammalian cells, CDK1 and CDK2 associate with various cyclin regulatory subunits. And these cyclin-CDK complexes are critical regulators of cell-cycle progression in neoplastic as well as normal cells. The authors examine the effect of CDK1 inhibition in tumor therapy. They select small-molecule inhibitor, Purvalanol and roscovitine, which can inhibit CDK1 function and induce G2 phase arrest. According to their study, they find that inhibition of CDK1 in cells that overexpress MYC led to apoptosis. This CDK1 inhibition–induced apoptosis is specific for MYC transformation, as cells transformed by a panel of other oncogenes could be arrested in G2 without induction of apoptosis in vitro and CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival in vivo. Moreover, They have identified survivin, a known substrate of CDK1, as a possible mediator of the apoptotic response to CDK inhibition and the depletion of survivin by small hairpin RNAs (shRNA) complementary to survivin could mimic CDK1 inhibitor treatment. Thus, the authors propose that CDK1 inhibition may prove useful in the treatment of human malignancies that overexpress MYC.

 

References:

1. Gray, N.S. et al. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 281, 533–538 (1998).

2. Yang, D., Welm, A. & Bishop, J.M. Cell division and cell survival in the absence of survivin. PNAS 101, 15100–15105 (2004).

3. Klefstrom, J., Verschuren, E.W. & Evan, G. c-Myc augments the apoptotic activity of cytosolic death receptor signaling proteins by engaging the mitochondrial apoptotic pathway. J. B. C. 277, 43224–43232 (2002).