The BCL2 antagonist of cell death pathway influences endometrial cancer cell sensitivity to cisplatin

Hye Sook Chon; Douglas C Marchion; Yin Xiong; Ning Chen; Elona Bicaku; Xiaomang Ba Stickles; Nadim Bou Zgheib; Patricia L Judson; Ardeshir Hakam; Jesus Gonzalez-Bosquet; Robert M Wenham; Sachin M Apte; Johnathan M Lancaster

doi:10.1016/j.ygyno.2011.09.020

Back

The BCL2 antagonist of cell death pathway influences endometrial cancer cell sensitivity to cisplatin

Journal article

Open access

Peer reviewed

The BCL2 antagonist of cell death pathway influences endometrial cancer cell sensitivity to cisplatin

Hye Sook Chon, Douglas C Marchion, Yin Xiong, Ning Chen, Elona Bicaku, Xiaomang Ba Stickles, Nadim Bou Zgheib, Patricia L Judson, Ardeshir Hakam, Jesus Gonzalez-Bosquet, …

Gynecologic Oncology, Vol.124(1), pp.119-124

01/2012

DOI: 10.1016/j.ygyno.2011.09.020

PMCID: PMC8744065

PMID: 22032837

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/8744065View

Open Access

Abstract

To identify pathways that influence endometrial cancer (EC) cell sensitivity to cisplatin and to characterize the BCL2 antagonist of cell death (BAD) pathway as a therapeutic target to increase cisplatin sensitivity. Eight EC cell lines (Ishikawa, MFE296, RL 95–2, AN3CA, KLE, MFE280, MFE319, HEC-1-A) were subjected to Affymetrix Human U133A GeneChip expression analysis of approximately 22,000 probe sets. In parallel, endometrial cell line sensitivity to cisplatin was quantified by MTS assay, and IC50 values were calculated. Pearson's correlation test was used to identify genes associated with response to cisplatin. Genes associated with cisplatin responsiveness were subjected to pathway analysis. The BAD pathway was identified and subjected to targeted modulation, and the effect on cisplatin sensitivity was evaluated. Pearson's correlation analysis identified 1443 genes associated with cisplatin resistance (P<0.05), which included representation of the BAD-apoptosis pathway. Small interfering RNA (siRNA) knockdown of BAD pathway protein phosphatase PP2C expression was associated with increased phosphorylated BAD (serine-155) levels and a parallel increase in cisplatin resistance in Ishikawa (P=0.004) and HEC-1-A (P=0.02) cell lines. In contrast, siRNA knockdown of protein kinase A expression increased cisplatin sensitivity in the Ishikawa (P=0.02) cell line. The BAD pathway influences EC cell sensitivity to cisplatin, likely via modulation of the phosphorylation status of the BAD protein. The BAD pathway represents an appealing therapeutic target to increase EC cell sensitivity to cisplatin. ► Endometrial cancer cell cisplatin-sensitivity is associated with the expression of the BAD pathway, likely via phosphorylation of BAD protein. ► Modulation of BAD phosphorylation by inhibition of BAD kinases and phosphatases influences endometrial cancer cell sensitivity to cisplatin-induced apoptosis. ► The BAD pathway represents an appealing therapeutic target to increase endometrial cancer cell sensitivity to cisplatin.

Endometrial cancer

Microarray gene analysis

Targeted therapy

BAD pathway

Cisplatin

Details

Title: Subtitle: The BCL2 antagonist of cell death pathway influences endometrial cancer cell sensitivity to cisplatin
Creators: Hye Sook Chon - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Douglas C Marchion - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Yin Xiong - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Ning Chen - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Elona Bicaku - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Xiaomang Ba Stickles - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Nadim Bou Zgheib - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Patricia L Judson - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Ardeshir Hakam - Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Jesus Gonzalez-Bosquet - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Robert M Wenham - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Sachin M Apte - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Johnathan M Lancaster - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Resource Type: Journal article
Publication Details: Gynecologic Oncology, Vol.124(1), pp.119-124
DOI: 10.1016/j.ygyno.2011.09.020
PMID: 22032837
PMCID: PMC8744065
NLM abbreviation: Gynecol Oncol
ISSN: 0090-8258
eISSN: 1095-6859
Publisher: Elsevier Inc
Grant note: The Sandra Ernst Fellowship Phi Beta Psi Sorority Ocala Royal Dames for Cancer Research, Inc.
Language: English
Date published: 01/2012
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9983930398202771

Metrics

38 Record Views

20 Times Cited - Web of Science