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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

CDK5 siRNA enhances the response to paclitaxel in HEY and A270 human ovarian cancer xenografts and CDK5 expression correlates inversely with ovarian cancer patient survival.(A) CDK5 siRNA-DOPC inhibited ovarian cancer xenograft growth and enhanced paclitaxel therapy in nu/nu mice. Groups of 10 mice were injected with HEY A8 or A2780 cancer cells and treated as described in Materials and Methods. Xenograft growth was measured by tumor weight on day 28 after tumor cell injection. (B) CDK5 expression correlated with patient survival. TMA Sections (215 patient samples) from department of Pathology were stained with specific antibody against CDK5. Repetitive CDK5 negative and positive images are shown in here. The relation between CDK5 expression level and prognosis was evaluated by Kaplan-Meier survival analysis.
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pone.0131833.g006: CDK5 siRNA enhances the response to paclitaxel in HEY and A270 human ovarian cancer xenografts and CDK5 expression correlates inversely with ovarian cancer patient survival.(A) CDK5 siRNA-DOPC inhibited ovarian cancer xenograft growth and enhanced paclitaxel therapy in nu/nu mice. Groups of 10 mice were injected with HEY A8 or A2780 cancer cells and treated as described in Materials and Methods. Xenograft growth was measured by tumor weight on day 28 after tumor cell injection. (B) CDK5 expression correlated with patient survival. TMA Sections (215 patient samples) from department of Pathology were stained with specific antibody against CDK5. Repetitive CDK5 negative and positive images are shown in here. The relation between CDK5 expression level and prognosis was evaluated by Kaplan-Meier survival analysis.

Mentions: To estimate the potential of CDK5 as a target for clinical therapy, the effect of CDK5 silencing was further tested in the HEYA8 and A2780 orthotopic mouse models of human ovarian cancer in Nu/Nu mice using the well-characterized DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) nanoliposomal delivery system [27, 28]. For each cancer cell line, 6 groups of 10 mice were treated for 4 weeks as follows: 1) DOPC nanoliposomes, 2) control siRNA-DOPC, 3) CDK5 siRNA-DOPC, 4) paclitaxel, or 5) a combination of control siRNA-DOPC plus paclitaxel, or 6) a combination of CDK5 siRNA-DOPC plus paclitaxel. CDK5 siRNA-DOPC plus paclitaxel produced greater inhibition of tumor growth than any other group for each of the two models (Fig 6A) and silencing CDK5 decreased p-AKT, increased TP53 and p27Kip1in vivo (S5 Fig).


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)

CDK5 siRNA enhances the response to paclitaxel in HEY and A270 human ovarian cancer xenografts and CDK5 expression correlates inversely with ovarian cancer patient survival.(A) CDK5 siRNA-DOPC inhibited ovarian cancer xenograft growth and enhanced paclitaxel therapy in nu/nu mice. Groups of 10 mice were injected with HEY A8 or A2780 cancer cells and treated as described in Materials and Methods. Xenograft growth was measured by tumor weight on day 28 after tumor cell injection. (B) CDK5 expression correlated with patient survival. TMA Sections (215 patient samples) from department of Pathology were stained with specific antibody against CDK5. Repetitive CDK5 negative and positive images are shown in here. The relation between CDK5 expression level and prognosis was evaluated by Kaplan-Meier survival analysis.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131833.g006: CDK5 siRNA enhances the response to paclitaxel in HEY and A270 human ovarian cancer xenografts and CDK5 expression correlates inversely with ovarian cancer patient survival.(A) CDK5 siRNA-DOPC inhibited ovarian cancer xenograft growth and enhanced paclitaxel therapy in nu/nu mice. Groups of 10 mice were injected with HEY A8 or A2780 cancer cells and treated as described in Materials and Methods. Xenograft growth was measured by tumor weight on day 28 after tumor cell injection. (B) CDK5 expression correlated with patient survival. TMA Sections (215 patient samples) from department of Pathology were stained with specific antibody against CDK5. Repetitive CDK5 negative and positive images are shown in here. The relation between CDK5 expression level and prognosis was evaluated by Kaplan-Meier survival analysis.
Mentions: To estimate the potential of CDK5 as a target for clinical therapy, the effect of CDK5 silencing was further tested in the HEYA8 and A2780 orthotopic mouse models of human ovarian cancer in Nu/Nu mice using the well-characterized DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) nanoliposomal delivery system [27, 28]. For each cancer cell line, 6 groups of 10 mice were treated for 4 weeks as follows: 1) DOPC nanoliposomes, 2) control siRNA-DOPC, 3) CDK5 siRNA-DOPC, 4) paclitaxel, or 5) a combination of control siRNA-DOPC plus paclitaxel, or 6) a combination of CDK5 siRNA-DOPC plus paclitaxel. CDK5 siRNA-DOPC plus paclitaxel produced greater inhibition of tumor growth than any other group for each of the two models (Fig 6A) and silencing CDK5 decreased p-AKT, increased TP53 and p27Kip1in vivo (S5 Fig).

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