Up-regulation of GADD45alpha expression by NSAIDs leads to apoptotic and necrotic colon cancer cell deaths.

Abstract

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.

• Authors: Shiun-Kwei Chiou, Neil Hoa
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 14 Issue 11 Pg. 1341-51 (Nov 2009) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 19757064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cell Cycle Proteins
• GADD45A protein, human
• Hydroxamic Acids
• Nuclear Proteins
• Oligonucleotides, Antisense
• RNA, Messenger
• Sulindac
• trichostatin A
• sulindac sulfide
• Indomethacin

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apoptosis (drug effects)
• Caco-2 Cells
• Cell Cycle Proteins (biosynthesis, genetics)
• Colonic Neoplasms (metabolism, pathology)
• Humans
• Hydroxamic Acids (pharmacology)
• Indomethacin (pharmacology)
• Necrosis (chemically induced)
• Nuclear Proteins (biosynthesis, genetics)
• Oligonucleotides, Antisense (pharmacology)
• RNA, Messenger (metabolism)
• Sulindac (analogs & derivatives, pharmacology)
• Up-Regulation (drug effects)