A novel pathway involving melanoma differentiation associated gene-7/interleukin-24 mediates nonsteroidal anti-inflammatory drug-induced apoptosis and growth arrest of cancer cells.

Abstract	Numerous studies show that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in chemoprevention or treatment of cancer. Nevertheless, the mechanisms underlying these antineoplastic effects remain poorly understood. Here, we report that induction of the cancer-specific proapoptotic cytokine melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) by several NSAIDs is an essential step for induction of apoptosis and G(2)-M growth arrest in cancer cells in vitro and inhibition of tumor growth in vivo. We also show that MDA-7/IL-24-dependent up-regulation of growth arrest and DNA damage inducible 45 alpha (GADD45alpha) and GADD45gamma gene expression is sufficient for cancer cell apoptosis via c-Jun NH(2)-terminal kinase (JNK) activation and growth arrest induction through inhibition of Cdc2-cyclin B checkpoint kinase. Knockdown of GADD45alpha and GADD45gamma transcription by small interfering RNA abrogates apoptosis and growth arrest induction by the NSAID treatment, blocks JNK activation, and restores Cdc2-cyclin B kinase activity. Our results establish MDA-7/IL-24 and GADD45alpha and GADD45gamma as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells.
Authors	Luiz F Zerbini, Akos Czibere, Yihong Wang, Ricardo G Correa, Hasan Otu, Marie Joseph, Yuko Takayasu, Moriah Silver, Xuesong Gu, Kriangsak Ruchusatsawat, Linglin Li, Devanand Sarkar, Jin-Rong Zhou, Paul B Fisher, Towia A Libermann
Journal	Cancer research (Cancer Res) Vol. 66 Issue 24 Pg. 11922-31 (Dec 15 2006) ISSN: 0008-5472 [Print] United States
PMID	17178890 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, 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 Culture Media GADD45A protein, human Interleukins Intracellular Signaling Peptides and Proteins Nuclear Proteins interleukin-24
Topics	Anti-Inflammatory Agents, Non-Steroidal (therapeutic use) Apoptosis (drug effects) Cell Cycle Proteins (genetics) Cell Differentiation (genetics) Cell Division (drug effects) Cell Line, Tumor Culture Media DNA Damage Humans Interleukins (genetics, physiology) Intracellular Signaling Peptides and Proteins (genetics) Male Nuclear Proteins (genetics) Polymerase Chain Reaction Prostatic Neoplasms (drug therapy, genetics, pathology) Transcription, Genetic GADD45 Proteins

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!