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Cancer Gene Ther. 2010 Feb;17(2):109-19. doi: 10.1038/cgt.2009.57. Epub 2009 Sep 4.

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

Author information

1
Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.

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.

PMID:
19730452
DOI:
10.1038/cgt.2009.57
[Indexed for MEDLINE]

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