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 p27Kip1 as well as TP53-dependent transcriptional induction of p21Cip1 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.
Highlights
In the United States in 2014 there were approximately 21,980 new cases of ovarian cancer and 14,270 deaths from this disease, consistent with a cure rate of only 30% for all stages
While knockdown of Cyclin-dependent kinase 5 (CDK5) with small interfering RNA (siRNA) could alter cell growth and paclitaxel sensitivity in ovarian cancer cell lines with mutant TP53 (EFO21, EFO27, IGROV1, CAOV3, OAW42 and ES-2, SKOv3 and OC316) (Fig 1A), the most marked effects were observed in two ovarian cancer cell lines with wild type TP53 (HEY and A2780) (Fig 1A and 1B)
To explore the additional mechanisms by which CDK5 silencing inhibits wild type TP53 ovarian cancer cell growth and enhanced paclitaxel sensitivity, we examined the effect of CDK5 knockdown with or without paclitaxel treatment on induction of apoptosis and cell cycle arrest in Hey cells which is TP53 wild type
Summary
In the United States in 2014 there were approximately 21,980 new cases of ovarian cancer and 14,270 deaths from this disease, consistent with a cure rate of only 30% for all stages. Type I “low grade” cancers grow slowly and are often detected in early stage. High grade ovarian cancers exhibit mutated TP53 as well as frequent abnormalities in homologous recombination repair of DNA and are driven by numerous DNA copy number abnormalities, but only very rarely by activating mutations. Both types of ovarian cancer are treated with cytoreductive surgery and a combination of drugs that includes carboplatin and paclitaxel. To enhance the efficacy of paclitaxel for treatment of ovarian cancer, we performed a kinome siRNA library screen in the presence and absence of paclitaxel to identify kinases that regulate paclitaxel sensitivity. Dysregulation of CDK5 has been linked to malignancy, including cancers of the prostate, pancreas, thyroid, lung, cervix, myeloma, and breast [6,7,8,9,10,11,12,13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
