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

Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.
Cancer Research (Impact Factor: 9.33). 09/2007; 67(15):7327-34. DOI: 10.1158/0008-5472.CAN-06-4766
Source: PubMed


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.

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Available from: Chang-Han Lee, Oct 29, 2015
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    • "Therefore, intensive studies on the tumor resistance mechanisms of TRAIL revealed that the failure of TRAIL to trigger apoptosis of tumor cells is associated with the cyto-protective effects of autophagy. Correspondingly, c-FLIP-expression is resistant to TRAIL-induced apoptosis and is characterized by the increase of Beclin-1 expression and a marked autophagosome formation in response to the activation of TRIAL or Fas receptors.240 Accordingly, the inhibition of the autophagic machinery in cells expressing c-FLIP or in Bax-deficient cells enhances their sensitivity to TRAIL-mediated cell death.234,235 "
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    • "For example, several inhibitors of mTOR62,63,64,65,66, tyrosine kinases67,68,69,70,71, Akt72,73,74 and activators of the cell energy sensor AMPK75,76 can lead to an induction of autophagy in cancer cells. Moreover, agents regulating cellular process such as the ubiquitin-proteasome77,78,79,80, histone deacetylation81,82,83,84,85,86,87, apoptosis88,89,90,91 and other therapies92,93,94,95,96,97 can also trigger autophagy in multiple tumor types as selectively described in Table 1. "
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