Novel mechanism of MDA-7/IL-24 cancer-specific apoptosis through SARI induction.

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.

• Authors: Rupesh Dash, Praveen Bhoopathi, Swadesh K Das, Siddik Sarkar, Luni Emdad, Santanu Dasgupta, Devanand Sarkar, Paul B Fisher
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 2 Pg. 563-74 (Jan 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24282278 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Basic-Leucine Zipper Transcription Factors
• Batf2 protein, human
• Interleukins
• Oligonucleotides, Antisense
• RNA, Messenger
• Tumor Suppressor Proteins
• interleukin-24
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis
• Basic-Leucine Zipper Transcription Factors (metabolism)
• Cell Proliferation
• Cell Survival
• Female
• Gene Expression Regulation, Neoplastic
• HeLa Cells
• Humans
• Interleukins (metabolism)
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neoplasms (metabolism)
• Oligonucleotides, Antisense (genetics)
• Phosphorylation
• RNA Processing, Post-Transcriptional
• RNA, Messenger (metabolism)
• Signal Transduction
• Tumor Suppressor Proteins (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)