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The 26S Proteasome as a Therapeutic Target in Cancer: Beyond Protease Inhibitors?

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Modulation of Protein Stability in Cancer Therapy

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Abstract

The 26S proteasome is a multi-subunit complex that has a barrel-shaped peptidase core (CP) whose proteolytic activity is sequestered from the cellular milieu by two regulatory particles (RP) that are docked on either end. The RP confers ubiquitin and ATP dependence to the proteolytic process. The CP can also be regulated by the REGγ complex, and can, in some instances, catalyze the degradation of proteins independent of ATP and ubiquitin. The peptidase activity of the 20S CP has been validated as a therapeutic target for cancers such as multiple myeloma by the development of inhibitors such as VELCAID. Since the peptidase activity is so central to 26S proteasome function, inhibitors of this class are generally toxic. Alternative therapeutic targets within the 26S proteasome can be explored, given the multistep nature of regulated degradation. Specifically, the recognition, and deubiquitination, of the polyubiquitin chain, and the unfolding and gating steps can be targeted.

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  1. Department of Biology, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, 91125, USA

    Rati Verma

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Eric Rubin Kathleen Sakamoto

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Verma, R. (2009). The 26S Proteasome as a Therapeutic Target in Cancer: Beyond Protease Inhibitors?. In: Rubin, E., Sakamoto, K. (eds) Modulation of Protein Stability in Cancer Therapy. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69147-3_2

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