Recombinant MDA-7/IL24 Suppresses Prostate Cancer Bone Metastasis through Downregulation of the Akt/Mcl-1 Pathway.

Abstract

Prostate cancer is a principal cause of cancer-associated morbidity in men. Although 5-year survival of patients with localized prostate cancer approaches 100%, survival decreases precipitously after metastasis. Bone is the preferred site for disseminated prostate cancer cell colonization, altering the equilibrium of bone homeostasis resulting in weak and fragile bones. Currently, no curative options are available for prostate cancer bone metastasis. Melanoma differentiation associated gene-7 (MDA-7)/IL24 is a well-studied cytokine established as a therapeutic in a wide array of cancers upon delivery as a gene therapy. In this study, we explored the potential anticancer properties of MDA-7/IL24 delivered as a recombinant protein. Using bone metastasis experimental models, animals treated with recombinant MDA-7/IL24 had significantly less metastatic lesions in their femurs as compared with controls. The inhibitory effects of MDA-7/IL24 on bone metastasis resulted from prostate cancer-selective killing and inhibition of osteoclast differentiation, which is necessary for bone resorption. Gain- and loss-of-function genetic approaches document that prosurvival Akt and Mcl-1 pathways are critically important in the antibone metastatic activity of MDA-7/IL24. Our previous findings showed that MDA-7/IL24 gene therapy plus Mcl-1 inhibitors cooperate synergistically. Similarly, an Mcl-1 small-molecule inhibitor synergized with MDA-7/IL24 and induced robust antibone metastatic activity. These results expand the potential applications of MDA-7/IL24 as an anticancer molecule and demonstrate that purified recombinant protein is nontoxic in preclinical animal models and has profound inhibitory effects on bone metastasis, which can be enhanced further when combined with an Mcl-1 inhibitory small molecule. Mol Cancer Ther; 17(9); 1951-60. ©2018 AACR.

• Authors: Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Luni Emdad, Swadesh K Das, Devanand Sarkar, Paul B Fisher
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 9 Pg. 1951-1960 (09 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 29934341 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Interleukins
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Recombinant Proteins
• Small Molecule Libraries
• interleukin-24
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Bone Neoplasms (genetics, immunology, secondary)
• Cell Line, Tumor
• Down-Regulation (drug effects, immunology)
• Gene Expression Regulation, Neoplastic (drug effects, immunology)
• Genetic Therapy (methods)
• Humans
• Interleukins (genetics, immunology, metabolism)
• Male
• Mice
• Mice, Nude
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, immunology, metabolism)
• Prostatic Neoplasms (genetics, immunology, pathology)
• Proto-Oncogene Proteins c-akt (genetics, immunology, metabolism)
• RAW 264.7 Cells
• Recombinant Proteins (genetics, immunology, metabolism)
• Signal Transduction (drug effects, genetics, immunology)
• Small Molecule Libraries (pharmacology)
• Xenograft Model Antitumor Assays (methods)