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Carcinogenesis Advance Access published online on April 5, 2006
Carcinogenesis, doi:10.1093/carcin/bgl027
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received November 17, 2005
Revised March 16, 2006
Accepted March 20, 2006

CANCER BIOLOGY

GADD153 mediates celecoxib-induced apoptosis in cervical cancer cells

Su-Hyeong Kim 1, Chang-Il Hwang 2, Woong-Yang Park 2, Je-Ho Lee 3, and Yong-Sang Song 4 *

1 Cancer Research Institute, Seoul National University College of Medicine, 28 Yungun-Dong, Chongno-Ku, Seoul 110-744, Korea
2 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 28 Yungun-Dong, Chongno-Ku, Seoul 110-744, Korea
3 Molecular Therapy Research Center, Samsung Medical Center, School of Medicine Sungkyunkwan University, 28 Yungun-Dong, Chongno-Ku, Seoul 110-744, Korea
4 Cancer Research Institute, Seoul National University College of Medicine, 28 Yungun-Dong, Chongno-Ku, Seoul 110-744, Korea; Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 28 Yungun-Dong, Chongno-Ku, Seoul 110-744, Korea

* To whom correspondence should be addressed.
Yong-Sang Song, E-mail: yssong{at}snu.ac.kr


  Abstract

Celecoxib, a selective cyclooxygenase 2 inhibitor, is known to have anti-inflammatory activity and to induce apoptosis in various types of cancer cells. Here, we examined the molecular mechanism of celecoxib-induced apoptosis in cervical cancer cell lines (HeLa, CaSki and C33A). Screening of a cDNA microarray chip containing 225 different genes revealed that GADD153, a transcription factor involved in apoptosis, showed the strongest differential expression following celecoxib treatment in all three cervical cancer cell lines. Notably, siRNA-induced silencing of GADD153 suppressed celecoxib-induced apoptosis in all three cell lines, and exogenous expression of GADD153 triggered apoptosis in cervical cancer cells in the absence of other apoptotic stimuli. A luciferse reporter gene assay and mRNA stability tests revealed that expression of GADD153 was regulated at both the transcriptional and posttranscriptional levels following celecoxib treatment. The region between -649 and -249, containing an intact C/EBP-ATF binding site, were required for celecoxib-induced stimulation of GADD153 promoter activity. In terms of signaling pathway, addition of the NF-{kappa}B inhibitor, TPCK, had no effect on GADD153 expression levels. Celecoxib treatment induced Bak expression, whereas cell transfected with siGADD153 showed lower levels of celecoxib-induced Bak up-regulation. These novel findings collectively suggest that GADD153 may play a key role in celecoxib-induced apoptosis in cervical cancer cells by regulating the expression of proapoptotic proteins such as Bak.

Keywords: GADD153; Bax; Cervical cancer.
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