Inhibition of autophagy induced by overexpression of mda-7/interleukin-24 strongly augments the antileukemia activity in vitro and in vivo.
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.
Yang
C
C
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.
Tong
Y
Y
Ni
W
W
Liu
J
J
Xu
W
W
Li
L
L
Liu
X
X
Meng
H
H
Qian
W
W
D000256:Adenoviridae / Q000235:genetics; D000730:Androstadienes / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy* / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D000077191:Wortmannin; D000099180:Interleukin-24
D000730:Androstadienes; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D007166:Immunosuppressive Agents; D007378:Interleukins; D008565:Membrane Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D000077191:Wortmannin; D000099180:Interleukin-24; C491997:BECN1 protein, human