GADD153 mediates celecoxib-induced apoptosis in cervical cancer cells

Carcinogenesis. 2007 Jan;28(1):223-31. doi: 10.1093/carcin/bgl227.


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 microarray cDNA-chip containing 225 different genes revealed that growth arrest and DNA damage inducible gene (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 the 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 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, was required for the basal activity and celecoxib-induced stimulation of GADD153 promoter activity. Also, mRNA stability test showed that celecoxib prolonged the half-life of GADD153 mRNA. In terms of signaling pathway, addition of the NF-kappaB inhibitor, N-tosyl-L phenylalanyl-chloromethyl ketone (TPCK), had no effect on GADD153 expression levels. Celecoxib treatment induced Bak expression, whereas cell treated with siGADD153 or TPCK 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.

Publication types

  • Corrected and Republished Article
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Celecoxib
  • Cyclooxygenase Inhibitors / pharmacology*
  • Female
  • Flow Cytometry
  • HeLa Cells / drug effects
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • Pyrazoles / pharmacology*
  • RNA Stability / drug effects
  • RNA, Messenger / analysis
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Sulfonamides / pharmacology*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*
  • Uterine Cervical Neoplasms / drug therapy*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism


  • BAK1 protein, human
  • Cyclooxygenase Inhibitors
  • DDIT3 protein, human
  • NF-kappa B
  • Pyrazoles
  • RNA, Messenger
  • RNA, Small Interfering
  • Sulfonamides
  • bcl-2 Homologous Antagonist-Killer Protein
  • Transcription Factor CHOP
  • Celecoxib