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A human scFv antibody against TRAIL receptor 2 induces autophagic cell death in both TRAIL-sensitive and TRAIL-resistant cancer cells.

Authors
Park, KJ; Lee, SH; Kim, TI; Lee, HW; Lee, CH; Kim, EH; Jang, JY; Choi, KS; Kwon, MH; Kim, YS
Citation
Cancer research, 67(15):7327-7334, 2007
Journal Title
Cancer research
ISSN
0008-54721538-7445
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptotic cell death in a variety of tumor cells without significant cytotoxicity on normal cells. However, many cancer cells with apoptotic defects are resistant to treatment with TRAIL alone, limiting its potential as an anticancer therapeutic. Here, we report on the tumoricidal activity of a human single-chain fragment variable, HW1, which specifically binds to TRAIL receptor 2 (TR2) without competing with TRAIL for the binding. HW1 treatment as a single agent induces autophagic cell death in a variety of both TRAIL-sensitive and TRAIL-resistant cancer cells, but exhibits much less cytotoxicity on normal cells. The HW1-induced autophagic cell death was inhibited by an autophagy inhibitor, 3-methyladenine, or by RNA interference knockdown of Beclin-1 and Atg7. We also show that the HW1-mediated autophagic cell death occurs predominantly via the c-Jun NH(2)-terminal kinase pathway in a caspase-independent manner. Analysis of the death-inducing signaling complex induced by HW1 binding to TR2 exhibits the recruitment of TNF receptor-associated death domain and TNF receptor-associated factor 2, but not Fas-associated death domain, caspase-8, or receptor-interacting protein, which is distinct from that induced by TRAIL. Our results reveal a novel TR2-mediated signaling pathway triggering autophagic cell death and provides a new strategy for the elimination of cancer cells, including TRAIL-resistant tumors, through nonapoptotic cell death.
MeSH terms
ApoptosisApoptosis Regulatory Proteins/antagonists & inhibitorsApoptosis Regulatory Proteins/geneticsApoptosis Regulatory Proteins/metabolismAutophagy*Blotting, WesternCaspases/metabolismCell SurvivalDrug Resistance, Neoplasm*Fas-Associated Death Domain Protein/metabolismHumansImmunoglobulin Fragments/immunology*Immunoglobulin Variable Region/immunology*ImmunoprecipitationJNK Mitogen-Activated Protein Kinases/metabolismMembrane Proteins/antagonists & inhibitorsMembrane Proteins/geneticsMembrane Proteins/metabolismMicroscopy, FluorescenceNeoplasms/metabolism*Neoplasms/pathologyRNA, Small Interfering/pharmacologyReceptors, TNF-Related Apoptosis-Inducing Ligand/immunology*Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolismReceptors, Tumor Necrosis Factor/metabolismRecombinant Fusion Proteins/geneticsRecombinant Fusion Proteins/metabolismSignal TransductionTNF-Related Apoptosis-Inducing Ligand/metabolism*Tumor Cells, CulturedTumor Necrosis Factor-alpha/metabolismUbiquitin-Activating Enzymes/antagonists & inhibitorsUbiquitin-Activating Enzymes/geneticsUbiquitin-Activating Enzymes/metabolism
DOI
10.1158/0008-5472.CAN-06-4766
PMID
17671202
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
최, 경숙권, 명희
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