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Targeting the extrinsic apoptosis signaling pathway for cancer therapy

  • Focussed Research Review
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The extrinsic apoptosis pathway is triggered by the binding of death ligands of the tumor necrosis factor (TNF) family to their appropriate death receptors (DRs) on the cell surface. One TNF family member, TNF-related apoptosis-inducing ligand (TRAIL or Apo2L), seems to preferentially cause apoptosis of transformed cells and can be systemically administered in the absence of severe toxicity. Therefore, there has been enthusiasm for the use of TRAIL or agonist antibodies to the TRAIL DR4 and DR5 in cancer therapy. Nonetheless, many cancer cells are very resistant to TRAIL apoptosis in vitro. Therefore, there is much interest in identifying compounds that can be combined with TRAIL to amplify its apoptotic effects. In this review, I will provide a brief overview of apoptosis signaling by TRAIL and discuss apoptosis-sensitizing agents, focusing mainly on the proteasome inhibitor bortezomib (VELCADE) and some novel sensitizers that we have recently identified. Alternative ways to administer TRAIL or DR agonist antibodies as therapeutic agents will also be described. Finally, I will discuss some of the gaps in our understanding of TRAIL apoptosis signaling and suggest some research directions that may provide additional information for optimizing the targeting of the extrinsic apoptosis pathway for future cancer therapy.

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Abbreviations

TRAIL:

TNF-related apoptosis-inducing ligand

c-FLIP:

Cellular FLICE-inhibitory protein

IAP:

Inhibitor of apoptosis protein

FADD:

Fas-associated death domain

DISC:

Death-inducing signaling complex

Smac/DAIBLO:

Second mitochondrial activator of caspases/direct IAP-binding protein with low pI

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Acknowledgments

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations implies endorsement by the US Government. This Research was supported [in part] by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Thanks to Alan Brooks, Candace Thompson, Richard Pompei, Drs Nancy Booth, and Curtis Henrich for their assistance with this work and Andrew Sayers for help with the artwork.

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  1. SAIC-Frederick, Inc., Laboratory of Experimental Immunology, Center for Cancer Research, Cancer and Inflammation Program, National Cancer Institute, Frederick, MD, 21702-1201, USA

    Thomas J. Sayers

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Correspondence to Thomas J. Sayers.

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This paper is a Focussed Research Review based on a presentation given at the Tenth International Conference on Progress in Vaccination against Cancer (PIVAC 10), held in St. Catharine’s College, Cambridge, UK, 27th–30th September 2010. It is part of a CII series of Focussed Research Reviews and meeting report.

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Sayers, T.J. Targeting the extrinsic apoptosis signaling pathway for cancer therapy. Cancer Immunol Immunother 60, 1173–1180 (2011). https://doi.org/10.1007/s00262-011-1008-4

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