Targeting the Ubiquitin-Proteasome Pathway: An Emerging Concept in Cancer Therapy

Selective degradation of proteins by the ubiquitin-proteasome pathway is a critical determinant for maintaining cellular homeostasis. Most intracellular proteins are degraded by the proteasome, a multicatalytic enzyme complex containing a 20S catalytic core and two 19S regulatory complexes. Many proteasome target proteins are involved in the regulation of important processes of carcinogenesis and cancer cell survival, such as cell cycle progression, cell proliferation, differentiation and apoptosis. Indeed, the ubiquitin-proteasome-dependent degradation pathway plays an essential role in both the up-regulation of cell proliferation and down-regulation of cell death in human cancer cells. Both in vitro and in vivo experimental and clinical results have demonstrated the potential use of proteasome inhibitors as novel anticancer drugs. Proteasome inhibition in cancer cells leads to accumulation of pro-apoptotic target proteins followed by induction of cell death. The clinical efficacy of the proteasome inhibitor bortezomib toward multiple myeloma and other hematologic malignancies provides the "proof of concept" that targeting the proteasome is a promising strategy for cancer treatment. Several other proteasome inhibitors have also been identified from natural resources, such as marine microbial metabolites, green tea polyphenols, flavonoids, and medicinal compounds. Additionally, the use of metal complexes as proteasome inhibitors has also been investigated as a potential anticancer strategy. The clinical significance of targeting the tumor survival-associated proteasome pathway for cancer treatment, intervention and prevention will be discussed.