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IAPs: from caspase inhibitors to modulators of NF-κB, inflammation and cancer

Nature Reviews Cancer volume 10, pages 561–574 (2010)Cite this article

Subjects

A Corrigendum to this article was published on 24 November 2010

Key Points

  • Alterations in inhibitor of apoptosis (IAP) proteins are prevalent in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis.

  • IAPs are best known for their ability to regulate caspases; however, IAPs also influence a multitude of other cellular processes.

  • Possibly the most important contribution of IAPs to cell survival and tumorigenesis resides in the ability of cIAP1, cIAP2 and XIAP to regulate ubiquitin-dependent activation of nuclear factor-κB (NF-κB) and innate immune responses.

  • Constitutive activation of NF-κB and chronic inflammation both have a major role in tumour development and are seen in most tumour types, including leukaemia, lymphomas and solid tumours.

  • NF-κB can be activated through the canonical and non-canonical signal transduction cascade, and cIAPs are crucial regulators of both these pathways.

  • cIAPs are also indispensable in protecting cancer cells from the lethal effects of tumour necrosis factor receptor 1 activation.

  • Small-molecule IAP antagonists, termed Smac mimetics, cause the rapid depletion of cIAPs and show potent anti-tumorigenic activity in vitro and in vivo.

Abstract

The realization that alterations in inhibitor of apoptosis (IAP) proteins are found in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis, has sparked a worldwide frenzy in the development of small pharmacological inhibitors of IAPs. The development of such inhibitors has radically changed our knowledge of the signalling processes that are regulated by IAPs. Recent studies indicate that IAPs not only regulate caspases and apoptosis, but also modulate inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis.

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Figure 1: Family association and domain characteristics.
Figure 2: IAP-mediated regulation of caspases: inhibition versus Ub-dependent inactivation.
Figure 3: IAPs function as E3 ligases in TNFR1-mediated activation of NF-κB.
Figure 4: Regulation of non-canonical NF-κB signalling.
Figure 5: IAPs in oncogenesis.
Figure 6: IAP-mediated regulation of innate immune responses.

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Acknowledgements

The authors would like to apologize to those whose work could not be cited or were cited only indirectly owing to space limitations. The authors would like to thank T. Nyman (BIR3-AVPI), M. Zvelebil (UBA) and C. Day (RING) for help with the structures, and members of the Meier Laboratory for helpful discussion and critical reading of the manuscript.

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Authors and Affiliations

  1. Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, DK2200, Copenhagen, Denmark

    Mads Gyrd-Hansen

  2. The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, SW3 6JB, London, UK

    Pascal Meier

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Glossary

Intrinsic apoptosis pathway

This pathway is dependent on mitochondria and is activated by developmental cues and cellular stresses such as DNA damage and oncogene activation. Pro-apoptotic BCL-2 family proteins facilitate the release of cytochrome c and other apoptogenic factors from the mitochondrial intermembrane space.

Extrinsic apoptosis pathway

This pathway is initiated on ligation of cell surface receptors of the TNFR superfamily. Activation of these receptors triggers the assembly of death-inducing signalling complexes that serve as a platform to activate caspase 8 and caspase 10.

Neo-amino-terminus

On proteolytic cleavage of a polypeptide, the amino acid immediately C terminal to the cleavage site becomes the new N terminal amino acid of the C terminal fragment.

Canonical pathway

Signals that predominantly activate the RELA–p50 heterodimers.

Non-canonical pathway

Signals that result in the activation of RELB–p52 heterodimers.

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Gyrd-Hansen, M., Meier, P. IAPs: from caspase inhibitors to modulators of NF-κB, inflammation and cancer. Nat Rev Cancer 10, 561–574 (2010). https://doi.org/10.1038/nrc2889

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