The ubiquitin-proteasome system as a prospective molecular target for cancer treatment and prevention

Abstract

Proteasomes are large multicatalytic proteinase complexes located in the cytosol and the nucleus of eukaryotic cells. The ubiquitin-proteasome system is responsible for the degradation of most intracellular proteins and therefore plays an essential regulatory role in critical cellular processes including cell cycle progression, proliferation, differentiation, angiogenesis and apoptosis. Besides involving in normal cellular functions and homeostasis, the alteration of proteasomal activity contributes to the pathological states of several clinical disorders including inflammation, neurodegeneration and cancer. It has been reported that human cancer cells possess elevated level of proteasome activity and are more sensitive to proteasome inhibitors than normal cells, indicating that the inhibition of the ubiquitin-proteasome system could be used as a novel approach for cancer therapy. In this review we summarize several specific aspects of research for the proteasome complex, including the structure and catalytic activities of the proteasome, properties and mechanisms of action of various proteasome inhibitors, and finally the clinical development of proteasome inhibitors as novel anticancer agents.

Fig. (1)

The ubiquitin-proteasome pathway. The ubiquitination of target proteins is mediated by Ub-activating (E1), Ub-conjugating (E2), and Ub-ligating (E3) enzymes. Substrate proteins tagged with a multiple-ubiquitin chain are degraded by a large 2000-kD protease complex called the 26S proteasome which is composed of a 20S catalytic core and two 19S caps.

Fig. (2)

20S proteasome. A, The cartoon shows a side view of 20S proteasome which possesses two outer α rings and two inner β rings. Each ring consists of seven α or seven β subunits. The catalytic activities of the β rings in 20S are found within the β1, β2, and β5 subunits. B, A cutaway stereoview of 20S proteasome shows the active sites (yellow) within the β rings. Adopted from Rechsteiner et al. Trends Cell Biol, 15:27–33, 2005, with permission from the Elsevier Ltd.

Fig. (3)

The ubiquitin-proteasome pathway is implicated in cell cycle regulation. Spk2 is an oncoprotein and a specific ubiquitin E3 ligase for p27. Spk2 is able to facilitate ubiquitination and degradation of the cell cycle inhibitor p27, resulting in cell cycle progression from G₁ to S phase. All p27, cyclin E, Rb and E2F proteins are proteasome targets.