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lüll A novel pathway involving melanoma differentiation associated gene-7/interleukin-24 mediates nonsteroidal anti-inflammatory drug-induced apoptosis and growth arrest of cancer cells Zerbini LF; Czibere A; Wang Y; Correa RG; Otu H; Joseph M; Takayasu Y; Silver M; Gu X; Ruchusatsawat K; Li L; Sarkar D; Zhou JR; Fisher PB; Libermann TACancer Res 2006[Dec]; 66 (24): 11922-31Numerous 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.|Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use[MESH]|Apoptosis/*drug effects[MESH]|Cell Cycle Proteins/genetics[MESH]|Cell Differentiation/genetics[MESH]|Cell Division/*drug effects[MESH]|Cell Line, Tumor[MESH]|Culture Media[MESH]|DNA Damage[MESH]|GADD45 Proteins[MESH]|Humans[MESH]|Interleukins/*genetics/physiology[MESH]|Intracellular Signaling Peptides and Proteins/genetics[MESH]|Male[MESH]|Nuclear Proteins/genetics[MESH]|Polymerase Chain Reaction[MESH]|Prostatic Neoplasms/drug therapy/genetics/pathology[MESH]|Transcription, Genetic[MESH] |