Anti-inflammatory Drug Associated Gene-7/Interleukin-24 Mediates Nonsteroidal A Novel Pathway Involving Melanoma Differentiation

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 G2-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 a (GADD45a) and GADD45g gene expression is sufficient for cancer cell apoptosis via c-Jun NH2-terminal kinase (JNK) activation and growth arrest induction through inhibition of Cdc2-cyclin B checkpoint kinase. Knockdown of GADD45a and GADD45g 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 GADD45A and GADD45; as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells. (Cancer Res 2006; 66(24): 11922-31)