Therapeutic anti-cancer targets upstream of the proteasome

Polyubiquitination of a protein is generally the first step in its degradation. This article discusses how altered protein destruction pathways impact the cell cycle and allow for abnormal cell proliferation, and explores how this process can be utilized in anticancer therapy. There are several levels of possible therapeutic intervention in ubiquitin-dependent proteolysis pathways upstream of the proteasome. In principle, targeting specific components of the ubiquitin system may offer an opportunity to develop selective drugs. However, the fact that general proteasome inhibitors have been demonstrated to be effective in cancer therapy suggests that other ubiquitin components that are common to many destruction pathways may also be clinically useful. We will, therefore, evaluate both the specific, rate-limiting enzymes and a number of general, nonselective enzymes as targets for anticancer therapy. Potential nonselective therapeutic strategies that are under investigation in a variety of human cancers include the identification and inhibition of individual F-box proteins, such as Skp2, and the inhibition of the ubiquitin ligases such as the SCF family, Mdm2, and Efp. A general pathway under investigation is the cullin neddylation and deneddylation system, with promising enzymatic targets such as csn5 and Rpn11.