Up-regulation of GADD45alpha expression by NSAIDs leads to apoptotic and necrotic colon cancer cell deaths.
Growth arrest and DNA damage inducible 45 alpha (GADD45alpha) is a central player in mediating apoptosis induced by a variety of stress stimuli and genotoxic agents. Regular usage of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and sulindac is associated with reduced risk for various cancers, including colon cancer. The role of GADD45alpha in NSAID-induced colon cancer cell cytotoxicity is unknown. In this study, we report that indomethacin and sulindac sulfide treatments up-regulate GADD45alpha mRNA expression and protein levels in colon cancer HT-29, RKO and Caco-2 cells. This up-regulation of GADD45alpha is accompanied by necrotic cell death and apoptosis. Anti-sense suppression of GADD45alpha expression inhibited indomethacin and sulindac sulfide-induced necrotic cell death and apoptosis. These findings confirm a role for GADD45alpha in NSAID-induced cytotoxicity, a mechanism for the anti-neoplastic effect of NSAIDs in colon tumorigenesis and cancer growth.
Chiou
Shiun-Kwei
SK
Department of Veterans Affairs Medical Center, Long Beach, CA 90822-5201, USA. skchiou@yahoo.com
Hoa
Neil
N
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D009336:Necrosis / Q000139:chemically induced*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000097642:GADD45 Proteins
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018797:Cell Cycle Proteins; D006877:Hydroxamic Acids; D007213:Indomethacin; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D013467:Sulindac; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C012589:trichostatin A; C025462:sulindac sulfide