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

Authors :
Dash, Rupesh
Bhoopathi, Praveen
Das, Swadesh K.
Sarkar, Siddik
Emdad, Luni
Dasgupta, Santanu
Sarkar, Devanand
Fisher, Paul B.
Source :
Cancer Research. 1/15/2014, Vol. 74 Issue 2, p563-574. 12p.
Publication Year :
2014

Abstract

Subtraction 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00085472
Volume :
74
Issue :
2
Database :
Academic Search Index
Journal :
Cancer Research
Publication Type :
Academic Journal
Accession number :
102912536
Full Text :
https://doi.org/10.1158/0008-5472.CAN-13-1062