Data from 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

<div>Abstract<p>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 (<i>MDA-7/IL-24</i>) by several NSAIDs is an essential step for induction of apoptosis and G<sub>2</sub>-M growth arrest in cancer cells <i>in vitro</i> and inhibition of tumor growth <i>in vivo</i>. We also show that MDA-7/IL-24–dependent up-regulation of <i>growth arrest and DNA damage inducible 45 α</i> (<i>GADD45α</i>) and <i>GADD45γ</i> gene expression is sufficient for cancer cell apoptosis via c-Jun NH<sub>2</sub>-terminal kinase (JNK) activation and growth arrest induction through inhibition of Cdc2-cyclin B checkpoint kinase. Knockdown of <i>GADD45α</i> and <i>GADD45γ</i> 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 GADD45α and GADD45γ as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells. (Cancer Res 2006; 66(24): 11922-31)</p></div>