BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin

Nisha Bansal, Douglas C. Marchion, Elona Bicaku, Yin Xiong, Ning Chen, Xiaomang B. Stickles, Entidhar Al Sawah, Robert M. Wenham, Sachin M. Apte, Jesus Gonzalez-Bosquet, Patricia L. Judson, Ardeshir Hakam, Johnathan M. Lancaster

Research output: Contribution to journalArticle

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Abstract

Objective: The BCL2 family proteins are critical mediators of cellular apoptosis and, as such, have been implicated as determinants of cancer cell chemo-sensitivity. Recently, it has been demonstrated that the phosphorylation status of the BCL2 antagonist of cell death (BAD) protein may influence ovarian cancer (OVCA) cell sensitivity to cisplatin. Here, we sought to evaluate how kinase and phosphatase components of the BAD apoptosis pathway influence OVCA chemo-sensitivity. Methods: Protein levels of cyclin-ependent kinase 1 (CDK1) and protein phosphatase 2C (PP2C) were measured by immuno fluorescence in a series of 64 primary advanced-stage serous OVCA patient samples. In parallel, levels of cAMP-dependent protein kinase (PKA), AKT, and PP2C were quantified by Western blot analysis in paired mother/daughter platinum-sensitive/resistant OVCA cell lines (A2008/C13, A2780S/A2780CP, Chi/ChiR). BAD pathway kinase CDK1 was depleted using siRNA transfection, and the influence on BAD phosphorylation and cisplatin-induced apoptosis was evaluated. Results: OVCA patient samples that demonstrated complete responses to primary platinum-based therapy demonstrated 4-fold higher CDK1 (p<0.0001) and 2-fold lower PP2C (p=0.14) protein levels than samples that demonstrated incomplete responses. Protein levels of PP2C were lower in the platinum-resistant versus that shown in the platinum-sensitive OVCA cell line sub-clones. Levels of PKA were higher in all platinum-resistant than in platinum-sensitive OVCA cell line sub-clones. Selective siRNA depletion of CDK1 increased sensitivity to cisplatin-induced apoptosis (p<0.002). Conclusion: BAD pathway kinases and phosphatases, including CDK1 and PP2C, are associated with OVCA sensitivity to platinum and may represent therapeutic opportunities to enhance cytotoxic efficacy.

Original languageEnglish (US)
Pages (from-to)35-42
Number of pages8
JournalJournal of Gynecologic Oncology
Volume23
Issue number1
DOIs
StatePublished - Mar 5 2012
Externally publishedYes

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Phosphoric Monoester Hydrolases
Ovarian Neoplasms
Cisplatin
Platinum
Cell Death
Phosphotransferases
Cyclins
Apoptosis
Cell Line
Small Interfering RNA
Proto-Oncogene Proteins c-bcl-2
Proteins
Clone Cells
Phosphorylation
Cyclic AMP-Dependent Protein Kinases
Nuclear Family
Protein Kinases
Transfection
Fluorescence
Western Blotting

Keywords

  • Bad apoptosis pathway
  • Cisplatin
  • Cyclin-dependent kinase 1
  • Ovarian cancer
  • Protein phosphatase 2c
  • Survival

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin. / Bansal, Nisha; Marchion, Douglas C.; Bicaku, Elona; Xiong, Yin; Chen, Ning; Stickles, Xiaomang B.; Sawah, Entidhar Al; Wenham, Robert M.; Apte, Sachin M.; Gonzalez-Bosquet, Jesus; Judson, Patricia L.; Hakam, Ardeshir; Lancaster, Johnathan M.

In: Journal of Gynecologic Oncology, Vol. 23, No. 1, 05.03.2012, p. 35-42.

Research output: Contribution to journalArticle

Bansal, N, Marchion, DC, Bicaku, E, Xiong, Y, Chen, N, Stickles, XB, Sawah, EA, Wenham, RM, Apte, SM, Gonzalez-Bosquet, J, Judson, PL, Hakam, A & Lancaster, JM 2012, 'BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin', Journal of Gynecologic Oncology, vol. 23, no. 1, pp. 35-42. https://doi.org/10.3802/jgo.2012.23.1.35
Bansal, Nisha ; Marchion, Douglas C. ; Bicaku, Elona ; Xiong, Yin ; Chen, Ning ; Stickles, Xiaomang B. ; Sawah, Entidhar Al ; Wenham, Robert M. ; Apte, Sachin M. ; Gonzalez-Bosquet, Jesus ; Judson, Patricia L. ; Hakam, Ardeshir ; Lancaster, Johnathan M. / BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin. In: Journal of Gynecologic Oncology. 2012 ; Vol. 23, No. 1. pp. 35-42.
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AU - Bansal, Nisha

AU - Marchion, Douglas C.

AU - Bicaku, Elona

AU - Xiong, Yin

AU - Chen, Ning

AU - Stickles, Xiaomang B.

AU - Sawah, Entidhar Al

AU - Wenham, Robert M.

AU - Apte, Sachin M.

AU - Gonzalez-Bosquet, Jesus

AU - Judson, Patricia L.

AU - Hakam, Ardeshir

AU - Lancaster, Johnathan M.

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N2 - Objective: The BCL2 family proteins are critical mediators of cellular apoptosis and, as such, have been implicated as determinants of cancer cell chemo-sensitivity. Recently, it has been demonstrated that the phosphorylation status of the BCL2 antagonist of cell death (BAD) protein may influence ovarian cancer (OVCA) cell sensitivity to cisplatin. Here, we sought to evaluate how kinase and phosphatase components of the BAD apoptosis pathway influence OVCA chemo-sensitivity. Methods: Protein levels of cyclin-ependent kinase 1 (CDK1) and protein phosphatase 2C (PP2C) were measured by immuno fluorescence in a series of 64 primary advanced-stage serous OVCA patient samples. In parallel, levels of cAMP-dependent protein kinase (PKA), AKT, and PP2C were quantified by Western blot analysis in paired mother/daughter platinum-sensitive/resistant OVCA cell lines (A2008/C13, A2780S/A2780CP, Chi/ChiR). BAD pathway kinase CDK1 was depleted using siRNA transfection, and the influence on BAD phosphorylation and cisplatin-induced apoptosis was evaluated. Results: OVCA patient samples that demonstrated complete responses to primary platinum-based therapy demonstrated 4-fold higher CDK1 (p<0.0001) and 2-fold lower PP2C (p=0.14) protein levels than samples that demonstrated incomplete responses. Protein levels of PP2C were lower in the platinum-resistant versus that shown in the platinum-sensitive OVCA cell line sub-clones. Levels of PKA were higher in all platinum-resistant than in platinum-sensitive OVCA cell line sub-clones. Selective siRNA depletion of CDK1 increased sensitivity to cisplatin-induced apoptosis (p<0.002). Conclusion: BAD pathway kinases and phosphatases, including CDK1 and PP2C, are associated with OVCA sensitivity to platinum and may represent therapeutic opportunities to enhance cytotoxic efficacy.

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KW - Survival

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