Immunoproteasome in Cancer and Neuropathologies: A New Therapeutic Target?

Elena Bellavista, Federico Andreoli, Marco Daniele Parenti, Morena Martucci, Aurelia Santoro,      Stefano Salvioli, Miriam Capri, Agostino Baruzzi, Alberto Del Rio, Claudio Franceschi, Michele Mishto

doi:10.2174/1381612811306040702

Abstract

Immunoproteasome is an emerging biological target that constitutes a key element not only in antigen presentation but also in T cell and cytokine regulation as well as cellular homeostasis. Respect to standard proteasome, the inducible expression and different sensitivity towards activity modulators of immunoproteasome render it a potential therapeutic target for tumours and central nervous system diseases. In this review we report the cutting edge studies for understanding when immunoproteasome expression is induced and how it regulates pivotal pathways involved in tumours and neuropathologies, including apoptosis and inflammation. We emphasize its role as a new pharmacological target by describing the recent medicinal chemistry efforts aimed at design selective small-molecule modulators of both standard- and immuno-proteasome forms. Finally, we also present an in silico model of the human immunoproteasome structure by the major molecular differences with the 20S standard proteasome and discuss the perspective for the design of novel specific smallmolecule modulators for the different proteasome isoforms.

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