• Rupesh Dash, Praveen Bhoopathi, Swadesh K Das, Siddik Sarkar, Luni Emdad, Santanu Dasgupta, Devanand Sarkar, and Paul B Fisher.
• Authors' Affiliations: Institute of Life Sciences, Bhubaneshwar, Orissa, India; Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, and VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
• Cancer Res. 2014 Jan 15; 74 (2): 563-74.

AbstractSubtraction hybridization combined with induction of cancer cell terminal differentiation in human melanoma cells identified melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) and SARI (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 mda-7/IL-24 (Ad.mda-7) or SARI (Ad.SARI) promotes cancer-specific cell death. Ectopic expression of mda-7/IL-24 induces SARI mRNA and protein in a panel of different cancer cells, leading to cell death, without harming corresponding normal cells. Simultaneous inhibition of K-ras downstream extracellular signal-regulated kinase 1/2 signaling in pancreatic cancer cells reverses the translational block of MDA-7/IL-24 and induces SARI expression and cell death. Using SARI-antisense-based approaches, we demonstrate that SARI expression is necessary for mda-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 SARI 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 SARI following Ad.mda-7 infection. These findings reveal the significance of the mda-7/IL-24-SARI axis in cancer-specific killing and provide a potential strategy for treating both local and metastatic disease.

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