Inhibition of autophagy induced by overexpression of mda-7/interleukin-24 strongly augments the antileukemia activity in vitro and in vivo.

Abstract

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel candidate of tumor suppressor that can selectively induce apoptosis experimentally in a spectrum of human cancer cells including leukemia cells. However, a recent study suggests that mda-7/IL-24 promotes the survival of chronic lymphocytic leukemia B-cells. In this study, we showed that mda-7/IL-24 was constitutively expressed in leukemia cell lines and primary acute myeloid leukemia samples. Using a conditionally replicating adenovirus expressing mda-7/IL-24 (ZD55-IL-24), we showed that enforced expression of mda-7/IL-24 in leukemia cells induced autophagy, which was triggered by the upregulation of Beclin-1. Immunofluorescence and coimmunoprecipitation studies suggested that mda-7/IL-24 protein interacts with Beclin-1. Class III PI3K/Beclin-1 complex was shown involved in the mda-7/IL-24-induced autophagy. Moreover, autophagy inhibition by phosphatidylinositol 3-kinase inhibitor, wortmannin, resulted in a reduced Beclin-1 expression and autophagosome formation associated with significantly enhanced cell death. Importantly, the combination of ZD55-IL-24 with wortmannin elicited a strongly enhanced antileukemia efficacy in established leukemia xenografts. These results suggest that mda-7/IL-24-induced autophagy in leukemia cells may provide survival advantage and mda-7/IL-24 combined with agents that disrupt autophagy is a promising new strategy for the treatment of leukemia.

• Authors: C Yang, Y Tong, W Ni, J Liu, W Xu, L Li, X Liu, H Meng, W Qian
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 17 Issue 2 Pg. 109-19 (Feb 2010) ISSN: 1476-5500 [Electronic] England
• PMID: 19730452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androstadienes
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Immunosuppressive Agents
• Interleukins
• Membrane Proteins
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering
• interleukin-24
• Wortmannin

Topics

• Adenoviridae (genetics)
• Androstadienes (pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy (genetics, physiology)
• Beclin-1
• Blotting, Western
• Cell Line, Tumor
• Female
• Genetic Vectors (genetics)
• Humans
• Immunoprecipitation
• Immunosuppressive Agents (pharmacology, therapeutic use)
• Interleukins (genetics, metabolism)
• Leukemia (drug therapy, therapy)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, SCID
• Microscopy, Electron, Transmission
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering
• Wortmannin