CDK5 Regulates Paclitaxel Sensitivity in Ovarian Cancer Cells by Modulating AKT Activation, p21Cip1- and p27Kip1-Mediated G1 Cell Cycle Arrest and Apoptosis.

Abstract

Cyclin-dependent kinase 5 (CDK5) is a cytoplasmic serine/ threonine kinase. Knockdown of CDK5 enhances paclitaxel sensitivity in human ovarian cancer cells. This study explores the mechanisms by which CDK5 regulates paclitaxel sensitivity in human ovarian cancers. Multiple ovarian cancer cell lines and xenografts were treated with CDK5 small interfering RNA (siRNA) with or without paclitaxel to examine the effect on cancer cell viability, cell cycle arrest and tumor growth. CDK5 protein was measured by immunohistochemical staining of an ovarian cancer tissue microarray to correlate CDK5 expression with overall patient survival. Knockdown of CDK5 with siRNAs inhibits activation of AKT which significantly correlates with decreased cell growth and enhanced paclitaxel sensitivity in ovarian cancer cell lines. In addition, CDK5 knockdown alone and in combination with paclitaxel induced G1 cell cycle arrest and caspase 3 dependent apoptotic cell death associated with post-translational upregulation and nuclear translocation of TP53 and p27(Kip1) as well as TP53-dependent transcriptional induction of p21(Cip1) in wild type TP53 cancer cells. Treatment of HEYA8 and A2780 wild type TP53 xenografts in nu/nu mice with CDK5 siRNA and paclitaxel produced significantly greater growth inhibition than either treatment alone. Increased expression of CDK5 in human ovarian cancers correlates inversely with overall survival. CDK5 modulates paclitaxel sensitivity by regulating AKT activation, the cell cycle and caspase-dependent apoptosis. CDK5 inhibition can potentiate paclitaxel activity in human ovarian cancer cells.

• Authors: Shu Zhang, Zhen Lu, Weiqun Mao, Ahmed A Ahmed, Hailing Yang, Jinhua Zhou, Nicholas Jennings, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Roberto Miranda, Wei Qiao, Veera Baladandayuthapani, Zongfang Li, Anil K Sood, Jinsong Liu, Xiao-Feng Le, Robert C Bast Jr
• Journal: PloS one (PLoS One) Vol. 10 Issue 7 Pg. e0131833 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26146988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclin-Dependent Kinase Inhibitor p27
• Cyclin-Dependent Kinase 5
• Proto-Oncogene Proteins c-akt
• CDK5 protein, human
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis
• Cell Line, Tumor
• Cyclin-Dependent Kinase 5 (genetics, physiology)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Enzyme Activation
• Female
• G1 Phase
• Humans
• Mice
• Mice, Nude
• Ovarian Neoplasms (pathology)
• Paclitaxel (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Xenograft Model Antitumor Assays