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

Zhang S, Lu Z, Mao W, Ahmed AA, Yang H, Zhou J, Jennings N, Rodriguez-Aguayo C, Lopez-Berestein G, Miranda R, Qiao W, Baladandayuthapani V, Li Z, Sood AK, Liu J, Le XF, Bast RC - PLoS ONE (2015)

Bottom Line: Cyclin-dependent kinase 5 (CDK5) is a cytoplasmic serine/ threonine kinase.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.CDK5 modulates paclitaxel sensitivity by regulating AKT activation, the cell cycle and caspase-dependent apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Departments of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Department of General Surgery, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

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.

No MeSH data available.


Related in: MedlinePlus

Knockdown of CDK5 inhibits activation of AKT in cancer cell lines.Western analysis for measuring inhibition of AKT phosphorylation (Ser473) using specific anti-p-AKT antibody. HEY cells were treated with control siRNA or CDK5 siRNA for 72 h. Cell lysates was subjected to immunoblot analysis.
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pone.0131833.g002: Knockdown of CDK5 inhibits activation of AKT in cancer cell lines.Western analysis for measuring inhibition of AKT phosphorylation (Ser473) using specific anti-p-AKT antibody. HEY cells were treated with control siRNA or CDK5 siRNA for 72 h. Cell lysates was subjected to immunoblot analysis.

Mentions: The phosphatidyinositol-3-kinase (PI3K)-Akt survival cascade is thought to be associated with the sensitivity to anticancer drugs. To explore the mechanism by which CDK5 silencing inhibited ovarian cancer cell growth and enhanced paclitaxel sensitivity, we first examined the effect of CDK5 knockdown on activation of AKT by detecting Ser473 phosphorylation of AKT. After treatment with CDK5 siRNA or control siRNA, Western analysis was performed. Silencing CDK5 significantly inhibited activation of AKT in 2 wild type TP53 (Fig 2) as well as in 4 of 8 mutant TP53 ovarian cancer cell lines (Fig 2). siRNAs inhibition of AKT activation in 6 ovarian cancer lines significantly correlates with decreased cell growth and enhanced paclitaxel sensitivity (Figs 1A and 2).


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

Zhang S, Lu Z, Mao W, Ahmed AA, Yang H, Zhou J, Jennings N, Rodriguez-Aguayo C, Lopez-Berestein G, Miranda R, Qiao W, Baladandayuthapani V, Li Z, Sood AK, Liu J, Le XF, Bast RC - PLoS ONE (2015)

Knockdown of CDK5 inhibits activation of AKT in cancer cell lines.Western analysis for measuring inhibition of AKT phosphorylation (Ser473) using specific anti-p-AKT antibody. HEY cells were treated with control siRNA or CDK5 siRNA for 72 h. Cell lysates was subjected to immunoblot analysis.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492679&req=5

pone.0131833.g002: Knockdown of CDK5 inhibits activation of AKT in cancer cell lines.Western analysis for measuring inhibition of AKT phosphorylation (Ser473) using specific anti-p-AKT antibody. HEY cells were treated with control siRNA or CDK5 siRNA for 72 h. Cell lysates was subjected to immunoblot analysis.
Mentions: The phosphatidyinositol-3-kinase (PI3K)-Akt survival cascade is thought to be associated with the sensitivity to anticancer drugs. To explore the mechanism by which CDK5 silencing inhibited ovarian cancer cell growth and enhanced paclitaxel sensitivity, we first examined the effect of CDK5 knockdown on activation of AKT by detecting Ser473 phosphorylation of AKT. After treatment with CDK5 siRNA or control siRNA, Western analysis was performed. Silencing CDK5 significantly inhibited activation of AKT in 2 wild type TP53 (Fig 2) as well as in 4 of 8 mutant TP53 ovarian cancer cell lines (Fig 2). siRNAs inhibition of AKT activation in 6 ovarian cancer lines significantly correlates with decreased cell growth and enhanced paclitaxel sensitivity (Figs 1A and 2).

Bottom Line: Cyclin-dependent kinase 5 (CDK5) is a cytoplasmic serine/ threonine kinase.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.CDK5 modulates paclitaxel sensitivity by regulating AKT activation, the cell cycle and caspase-dependent apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Departments of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Department of General Surgery, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

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.

No MeSH data available.


Related in: MedlinePlus