title: GADD153 mediates celecoxib-induced apoptosis in cervical cancer cells.
abstract: Celecoxib, a selective cyclooxygenase-2 inhibitor, is known to possess anti-inflammatory activity and also induces 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 (growth arrest and DNA damage inducible gene), 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 luciferase reporter gene assay and mRNA stability tests revealed that the expression of GADD153 was regulated at both the transcriptional and post-transcriptional levels following celecoxib treatment. The region between -649 and -249, containing an intact C/EBP-ATF binding site, is required for celecoxib-induced stimulation of GADD153 promoter activity. In terms of signaling pathway, addition of the NF-kappaB inhibitor, N-tosyl-L-phenylalanyl-chloromethyl ketone, had no effect on GADD153 expression levels. Celecoxib treatment induced Bak expression, whereas cell transfected with siGADD153 showed lower levels of celecoxib-induced Bak upregulation. 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.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Chongno-Ku, Seoul 110-744, Korea.
authors.forename: Su-Hyeong
authors.initials: SH
authors.lastname: Kim
authors.forename: Chang-Il
authors.initials: CI
authors.lastname: Hwang
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.forename: Je-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Yong-Sang
authors.initials: YS
authors.lastname: Song
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics
chemical_list: C494772:BAK1 protein, human; D052246:Cyclooxygenase 2 Inhibitors; C497249:DDIT3 protein, human; D016328:NF-kappa B; D011720:Pyrazoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051742:Transcription Factor CHOP; D000068579:Celecoxib