Data from Novel Mechanism of MDA-7/IL-24 Cancer-Specific Apoptosis through SARI Induction

Abstract

<div>Abstract<p>Subtraction hybridization combined with induction of cancer cell terminal differentiation in human melanoma cells identified melanoma differentiation–associated gene-7/interleukin-24 (<i>mda-7</i>/IL-24) and <i>SARI</i> (suppressor of AP-1, induced by IFN) that display potent antitumor activity. These genes are not constitutively expressed in cancer cells and forced expression of <i>mda-7</i>/IL-24 (Ad.<i>mda-7</i>) or <i>SARI</i> (Ad.<i>SARI</i>) promotes cancer-specific cell death. Ectopic expression of <i>mda-7</i>/IL-24 induces <i>SARI</i> mRNA and protein in a panel of different cancer cells, leading to cell death, without harming corresponding normal cells. Simultaneous inhibition of K-<i>ras</i> downstream extracellular signal-regulated kinase 1/2 signaling in pancreatic cancer cells reverses the translational block of MDA-7/IL-24 and induces <i>SARI</i> expression and cell death. Using <i>SARI</i>-antisense-based approaches, we demonstrate that <i>SARI</i> expression is necessary for <i>mda</i>-7/IL-24 antitumor effects. Secreted MDA-7/IL-24 protein induces antitumor “bystander” effects by promoting its own expression. Recombinant MDA-7/IL-24 (His-MDA-7) induces <i>SARI</i> expression, supporting the involvement of SARI in the MDA-7/IL-24-driven autocrine loop, culminating in antitumor effects. Moreover, His-MDA-7, after binding to its cognate receptors (IL-20R1/IL-20R2 or IL-22R/IL-20R2), induces intracellular signaling by phosphorylation of p38 MAPK, leading to transcription of a family of growth arrest and DNA damage inducible (GADD) genes, culminating in apoptosis. Inhibition of p38 MAPK fails to induce <i>SARI</i> following Ad.<i>mda</i>-7 infection. These findings reveal the significance of the <i>mda</i>-7/IL-24-<i>SARI</i> axis in cancer-specific killing and provide a potential strategy for treating both local and metastatic disease. <i>Cancer Res; 74(2); 563–74. ©2013 AACR</i>.</p></div>