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Introduction to the Proteasome and its Inhibitors

Biochemistry and Cell Biology

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Proteasome Inhibitors in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

The development of proteasome inhibitors for treatment of multiple myeloma and probably other cancers has followed an unusual course but is clearly linked to recent basic advances in our understanding of intracellular protein breakdown. After the discovery of the ATP-dependent pathway for protein degradation in the 1970s, ATP was shown necessary for the conjugation of ubiquitin to cell proteins, which marks them for degradation by the 26S proteasome. Its 19S regulatory complex uses ATP to unfold proteins and to inject them into the 20S core proteasome where proteins are digested to small peptides. The active sites in the 20S proteasome function by a novel threonine-based mechanism which allows their selective inhibition (e.g., by the boronate, Velcade). Surprisingly, we initially organized a biotechnology company to develop inhibitors of the ubiquitin—proteasome pathway not for cancer therapy, but with the goal of reducing the excessive proteolysis seen in atrophying muscle or cachexia, as well as inhibition of MHC class I antigen presentation, both of which depend on proteasome function. The availability of proteasome inhibitors has greatly advanced our understanding of the many functions of the proteasome, such as its key role in the activation of the transcription factor NF-κB, which led to a recognition that proteasome inhibitors might have anti-inflammatory and antineoplastic actions. The unexpected discovery that these inhibitors cause apoptosis selectively in neoplastic cells led to systematic studies and clinical trials against cancer. Amongst their multiple actions, proteasome inhibitors (1) cause the accumulation of abnormal proteins, which can trigger apoptosis; (2) stabilize tumor suppressors (p53, p27); (3) inhibit production of NF-κB, which is antiapoptic and generates important growth factors and cell adhesion molecules. However, the actual importance of these mechanisms in vivo in combating cancer remains uncertain.

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Authors
  1. Alfred L. Goldberg
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  1. Infinity Pharmaceuticals Inc., Cambridge, MA, USA

    Julian Adams PhD

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Goldberg, A.L. (2004). Introduction to the Proteasome and its Inhibitors. In: Adams, J. (eds) Proteasome Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-794-9_2

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  • DOI: https://doi.org/10.1007/978-1-59259-794-9_2

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-452-4

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