Focal adhesion kinase silencing augments docetaxel-mediated apoptosis in ovarian cancer cells

Jyotsnabaran HALDER; Charles N LANDEN; Susan K LUTGENDORF; Yang Li; Nicholas B JENNINGS; Dominic FAN; Gina M NELKIN; Rosemarie SCHMANDT; Michael D SCHALLER; Anil K SOOD

doi:10.1158/1078-0432.CCR-05-1728

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Focal adhesion kinase silencing augments docetaxel-mediated apoptosis in ovarian cancer cells

Journal article

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Focal adhesion kinase silencing augments docetaxel-mediated apoptosis in ovarian cancer cells

Jyotsnabaran HALDER, Charles N LANDEN, Susan K LUTGENDORF, Yang Li, Nicholas B JENNINGS, Dominic FAN, Gina M NELKIN, Rosemarie SCHMANDT, Michael D SCHALLER and Anil K SOOD

Clinical cancer research, Vol.11(24), pp.8829-8836

2005

DOI: 10.1158/1078-0432.CCR-05-1728

PMCID: PMC3144933

PMID: 16361572

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Abstract

Objective: Docetaxel causes cell death through induction of apoptosis; however, cell death characteristics for docetaxel have not yet been fully elucidated. We examined the role of focal adhesion kinase (FAK) cleavage in docetaxel-mediated apoptosis. Methods: FAK degradation after treatment with docetaxel was determined in both taxane-sensitive (HeyA8 and SKOV3) and taxane-resistant (HeyA8-MDR and SKOV3-TR) ovarian cancer cell lines by Western blot analysis. Cell growth was determined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. FAK-targeting small interfering RNA (siRNA) was used to decrease FAK expression. Apoptosis and caspase activity were determined using commercially available kits. Results: SKOV3 and HeyA8 cell lines were both sensitive to docetaxel (IC50 levels, 1-6.2 nmol/L), whereas the SKOV3-TR and HeyA8-MDR cells were resistant (IC50 ≥ 250 nmol/L for both). Docetaxel induced high rates of apoptosis in SKOV3 and HeyA8 cells (84% and 66% apoptosis, respectively) but minimal apoptosis (5-8%) in SKOV3-TR and HeyA8-MDR cells. Similarly, FAK was cleaved in SKOV3 and HeyA8 cells in response to docetaxel treatment but unchanged in the resistant cells. Caspase-3 and caspase-8 activity also increased significantly in docetaxel-treated SKOV3 and HeyA8 cells but not in the taxane-resistant cells. DEVD-fmk (caspase-3 blocker) was able to block both FAK cleavage and apoptosis mediated by docetaxel in SKOV3 and HeyA8 cells. FAK siRNA transfection resulted in 70% to 90% decrease in FAK levels in all cell lines within 72 hours. FAK silencing augmented docetaxel-mediated growth inhibition (5- to 8-fold increase) and apoptosis in both of the taxane-sensitive and taxane-resistant cell lines. Conclusions: Docetaxel induces FAK cleavage, mediated through activation of caspase-3, in taxane-sensitive ovarian cancer cells but not in taxane-resistant cells. The absence of FAK degradation may contribute to cell survival in taxane-resistant cells. FAK silencing promotes the in vitro efficacy of docetaxel in both taxane-sensitive and taxane-resistant cell lines and may serve as a novel therapeutic approach.

Antineoplastic Agents

Tumors

Gynecology. Andrology. Obstetrics

Pharmacology. Drug treatments

Biological and medical sciences

Medical sciences

Female genital diseases

Details

Title: Subtitle: Focal adhesion kinase silencing augments docetaxel-mediated apoptosis in ovarian cancer cells
Creators: Jyotsnabaran HALDER - Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States
Charles N LANDEN - Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States
Susan K LUTGENDORF - Department of Psychology, University of Iowa, Iowa City, Iowa, United States
Yang Li - Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States
Nicholas B JENNINGS - Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States
Dominic FAN - Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States
Gina M NELKIN - Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States
Rosemarie SCHMANDT - Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States
Michael D SCHALLER - Department of Cell and Developmental Biology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States
Anil K SOOD - Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.11(24), pp.8829-8836
DOI: 10.1158/1078-0432.CCR-05-1728
PMID: 16361572
PMCID: PMC3144933
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Publisher: American Association for Cancer Research; Philadelphia, PA
Language: English
Date published: 2005
Academic Unit: Psychological and Brain Sciences; Iowa Neuroscience Institute; Obstetrics and Gynecology; Urology
Record Identifier: 9984065884302771

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