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.

8 Reads
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Both apoptosis and autophagy are highly conserved processes that besides their role in the maintenance of the organismal and cellular homeostasis serve as a main target of tumor therapeutics. Although their important roles in the modulation of tumor therapeutic strategies have been widely reported, the molecular actions of both apoptosis and autophagy are counteracted by cancer protective mechanisms. While apoptosis is a tightly regulated process that is implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in lysosomal degradation and recycling of proteins and organelles, and thereby is considered an important survival/protective mechanism for cancer cells in response to metabolic stress or chemotherapy. Although the relationship between autophagy and cell death is very complicated and has not been characterized in detail, the molecular mechanisms that control this relationship are considered to be a relevant target for the development of a therapeutic strategy for tumor treatment. In this review, we focus on the molecular mechanisms of apoptosis, autophagy, and those of the crosstalk between apoptosis and autophagy in order to provide insight into the molecular mechanisms that may be essential for the balance between cell survival and death as well as their role as targets for the development of novel therapeutic approaches.
    Journal of Cell Death 08/2013; 6(1):37-55. DOI:10.4137/JCD.S11034
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy, an evolutionarily conserved catabolic process involving the engulfment and degradation of non-essential or abnormal cellular organelles and proteins, is crucial for homeostatic maintenance in living cells. This highly regulated, multi-step process has been implicated in diverse diseases including cancer. Autophagy can function as either a promoter or a suppressor of cancer, which makes it a promising and challenging therapeutic target. Herein, we overview the regulatory mechanisms and dual roles of autophagy in cancer. We also describe some of the representative agents that exert their anticancer effects by regulating autophagy. Additionally, some emerging strategies aimed at modulating autophagy are discussed as having the potential for future anticancer drug discovery. In summary, these findings will provide valuable information to better utilize autophagy in the future development of anticancer therapeutics that meet clinical requirements.
    Acta Pharmacologica Sinica 04/2013; 34(5). DOI:10.1038/aps.2013.23 · 2.91 Impact Factor
  • Source
    • "Double labeling immunohistochemistry (Fig. 4E) with BrdU (green) and Iba1 (red) antibodies instead revealed that in the cortex newborn cells around amyloid plaques had differentiated into microglial cells. In the AD brain, oxidative stress and the inflammatory reaction work together in the pathogenic cascade leading to neurodegeneration [24]. Microglia and astrocytes activated by A␤ produce and secrete chemokines, various pro-inflammatory cytokines, reactive oxygen species and NO that may result in neuronal damage [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to investigate the microglia-driven apoptosis and the Aβ deposits triggered generation of new microglial cells in the neocortex of TgCRND8 mice. Three- and seven-month-old TgCRND8 mice, displaying an early and widespread amyloid deposition, respectively, were used. In 7-month-old TgCRND8 mice the Aβ-associated glial reaction was accompanied by an intense immunoreactivity of both TNF-α and inducible nitric oxide synthase, increased immunoreactivity of the pro-apoptotic protein Bax and a decrease in levels of the anti-apoptotic protein Bcl-2.Cortical and hippocampal neurons of TgCRND8 mice displayed higher immunoreactivity and higher nuclear expression of the transcription factor NF-kB than controls. It is possible that such an increase could represent a defence/compensatory response to degeneration. These findings indicate that Aβ deposits activate brain-resident microglia population and astrocytes, and induce overproduction of inflammatory mediators that enhance pro- and anti-apoptotic cascades. In both 3- and 7-month-old TgCRND8 mice apparent gliogenesis was present in the vicinity of Aβ plaques in the neocortex, indicating that microglia have a high proliferative rate which might play a more complex role than previously acknowledge.
    Neuroscience Letters 10/2011; 506(1):94-9. DOI:10.1016/j.neulet.2011.10.056 · 2.03 Impact Factor
Show more


8 Reads
Available from