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Novel mechanism of MDA-7/IL-24 cancer-specific apoptosis through SARI induction
Rupesh Dash1, Praveen Bhoopathi, Swadesh K Das
1Authors' 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.
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.
Insights
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) and SARI show potent antitumor activity by inducing cancer-specific cell death. The mda-7/IL-24-SARI axis is crucial for these anticancer effects.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) and Suppressor of AP-1, induced by IFN (SARI) exhibit antitumor properties.
- These genes are not inherently present in cancer cells and require forced expression for therapeutic effects.
Purpose of the Study:
- To investigate the antitumor mechanisms of mda-7/IL-24 and SARI.
- To elucidate the relationship between mda-7/IL-24 and SARI in cancer cell death.
- To explore the potential of the mda-7/IL-24-SARI axis as a cancer treatment strategy.
Main Methods:
- Subtraction hybridization and induction of terminal differentiation in melanoma cells.
- Gene expression analysis of mda-7/IL-24 and SARI in cancer cells.
- Inhibition of K-ras downstream signaling and p38 MAPK pathway.
- SARI-antisense approaches and recombinant protein studies.
Main Results:
- Forced expression of mda-7/IL-24 or SARI induces cancer-specific cell death without harming normal cells.
- Ectopic mda-7/IL-24 expression upregulates SARI, leading to cell death, and this effect is necessary for mda-7/IL-24's antitumor activity.
- MDA-7/IL-24 triggers an autocrine loop involving SARI and activates p38 MAPK signaling, inducing GADD genes and apoptosis.
Conclusions:
- The mda-7/IL-24-SARI axis plays a significant role in cancer-specific killing.
- Targeting this axis offers a potential therapeutic strategy for both local and metastatic cancers.
- MDA-7/IL-24's ability to induce SARI and trigger apoptosis pathways highlights its therapeutic potential.
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