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A Novel Pathway Involving Melanoma Differentiation Associated Gene-7/Interleukin-24 Mediates Nonsteroidal Anti-inflammatory Drug–Induced Apoptosis and Growth Arrest of Cancer Cells

¹ BIDMC Genomics Center and ² Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; ³ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California; and ⁴ Departments of Pathology and Urology, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York

Requests for reprints: Towia A. Libermann, BIDMC Genomics Center and Dana-Farber/Harvard Cancer Center Cancer Proteomics Core, Beth Israel Deaconess Medical Center and Harvard Medical School, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115. Phone: 617-667-3393; Fax: 617-975-5299; E-mail: tliberma{at}bidmc.harvard.edu.

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 (GADD45) and GADD45 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 GADD45 and GADD45 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 GADD45 and GADD45 as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells. (Cancer Res 2006; 66(24): 11922-31)

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