title: Eponemycin exerts its antitumor effect through the inhibition of proteasome function.
abstract: 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.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520-8103, USA.
authors.forename: L
authors.initials: L
authors.lastname: Meng
authors.forename: B H
authors.initials: BH
authors.lastname: Kwok
authors.forename: N
authors.initials: N
authors.lastname: Sin
authors.forename: C M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000502:physiology; D046988:Proteasome Endopeptidase Complex; D012694:Serine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000577:Amides; D000903:Antibiotics, Antineoplastic; D009097:Multienzyme Complexes; C063282:eponemycin; D012694:Serine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex