Dai, L,Liu, YQ,Liu, JY,Wen, XM,Xu, ZS,Wang, Z,Sun, H,Tang, SB,Maguire, AR,Quan, JM,Zhang, H,Ye, T

2013

June

Cancer Letters

A novel CyclinE/CyclinA-CDK Inhibitor targets p27(Kip1) degradation, cell cycle progression and cell survival: Implications in cancer therapy

Validated

WOS: 43 ()

p27(Kip1) CyclinE/CyclinA-CDK Inhibitor Cell cycle Proliferation Apoptosis DEPENDENT-KINASE INHIBITOR UBIQUITIN-MEDIATED DEGRADATION P27 PHOSPHORYLATION COMPLEX E-CDK2 CKS1

333

103

112

p27(Kip1) (p27) binds and inhibits the cyclin E- or cyclin A-associated cyclin-dependent kinases (CDKs)2 and other CDKs, and negatively regulates G1-G2 cell cycle progression. To develop specific CDK inhibitors, we have modeled the interaction between p27 and cyclin A-CDK2, and designed a novel compound that mimics p27 binding to cyclin A-CDK2. The chemically synthesized inhibitor exhibited high potency and selective inhibition towards cyclin E/cyclin A-CDK2 kinase in vitro but not other kinases. To facilitate permeability of the inhibitor, a cell penetrating peptide (CPP) was conjugated to the inhibitor to examine its effect in several cancer cell lines. The CPP-conjugated inhibitor significantly inhibited the proliferation of cancer cells. The treatment of the inhibitor resulted in the increased accumulation of p27 and p21(Cip1/Waf1) (p21) and hypo-phosphorylation of retinoblastoma protein (Rb). The degradation of p27, mediated through the phosphorylation of threonine-187 in p27, was also inhibited. Consequently, exposure of cells to the inhibitor caused cell cycle arrest and apoptosis. We conclude that specific cyclinE/cyclin A-CDK2 inhibitors can be developed based on the interaction between p27 and cyclin/CDK to block cell cycle progression to prevent tumor growth and survival. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

10.1016/j.canlet.2013.01.025