Exploiting the ubiquitin-proteasome pathway for anticancer drug discovery: Unanswered questions and future directions

The ubiquitin-proteasome pathway is a dynamic and complex cellular process that regulates the levels of 80-90% of the proteins in the cell. To date, most of the pharmacological development for manipulation of this pathway has centered on inhibition of the active sites in the 20S proteasome. However, there are many other targets available for drug development in the ubiquitin-proteasome pathway. Each target could differentially effect protein degradation and cellular responses. This review examines the potential points of regulation within ubiquitin-proteasome pathway that could lead to changes within specific subpopulations of proteins. Such a specific inhibition of the proteasome pathway could provide a host of new therapies with more predictable and controllable toxicities. Furthermore, this review discusses the participation of individual proteins, as well as the protein network, to elicit the cellular responses induced by proteasome inhibitors.