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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Zobel, Kerry Wong, Harvey Alicke, Bruno Gould, Stephen E. Vucic, Domagoj Fairbrother, Wayne J. Scheer, Justin M. Elliott, J. Michael Ashkenazi, Avi Varfolomeev, Eugene West, Kristina |
| Description | Author Affiliation: Varfolomeev E ( Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA.) |
| Abstract | Proapoptotic receptor agonists cause cellular demise through the activation of the extrinsic and intrinsic apoptotic pathways. Inhibitor of apoptosis (IAP) proteins block apoptosis induced by diverse stimuli. Here, we demonstrate that IAP antagonists in combination with Fas ligand (FasL) or the death receptor 5 (DR5) agonist antibody synergistically stimulate death in cancer cells and inhibit tumor growth. Single-agent activity of IAP antagonists relies on tumor necrosis factor-alpha signaling. By contrast, blockade of tumor necrosis factor-alpha does not affect the synergistic activity of IAP antagonists with FasL or DR5 agonist antibody. In most cancer cells, proapoptotic receptor agonist-induced cell death depends on amplifying the apoptotic signal via caspase-8-mediated activation of Bid and subsequent activation of the caspase-9-dependent mitochondrial apoptotic pathway. In the investigated cancer cell lines, induction of apoptosis by FasL or DR5 agonist antibody can be inhibited by knockdown of Bid. However, knockdown of X chromosome-linked IAP (XIAP) or antagonism of XIAP allows FasL or DR5 agonist antibody to induce activation of effector caspases efficiently without the need for mitochondrial amplification of the apoptotic signal and thus rescues the effect of Bid knockdown in these cells. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 50 |
| Volume Number | 284 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2009-12-11 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Physiology Cell Death Fas Ligand Protein Metabolism Receptors, TNF-Related Apoptosis-Inducing Ligand Agonists X-Linked Inhibitor Of Apoptosis Protein Antagonists & Inhibitors Animals BH3 Interacting Domain Death Agonist Protein Genetics Caspases Cell Line, Tumor Etanercept Immunoglobulin G Mice RNA, Small Interfering Receptors, Tumor Necrosis Factor Signal Transduction Transplantation, Heterologous Tumor Necrosis Factor-alpha Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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