Eponemycin exerts its antitumor effect through the inhibition of proteasome function

Cell cycle progression requires the proteasome-mediated degradation of key regulatory proteins such as cyclins, cyclin-dependent kinase inhibitors, and anaphase-inhibitory proteins. Given the central role of the Proteasome in the destruction of these proteins, Proteasome inhibition has been proposed as a possible Cancer therapy. We report here that dihydroeponemycin, an analogue of the antitumor and antiangiogenic natural product eponemycin, selectively targets the 20S Proteasome. Dihydroeponemycin covalently modifies a subset of catalytic proteasomal subunits, binding preferentially to the IFN-gamma-inducible subunits LMP2 and LMP7. Moreover, the three major peptidolytic activities of the Proteasome are inhibited by dihydroeponemycin at different rates. In addition, dihydroeponemycin-mediated Proteasome inhibition induces a spindle-like cellular morphological change and Apoptosis. These results validate the Proteasome as a target for antitumor pharmacological intervention and are relevant for the design of novel chemotherapeutic strategies.