Details

Autor(en) / Beteiligte

• LIHAO MENG
• KWOK, B. H. B
• NY SIN
• CREWS, C. M

Titel

Eponemycin exerts its antitumor effect through the inhibition of proteasome function

Ist Teil von

• Cancer research (Chicago, Ill.), 1999-06, Vol.59 (12), p.2798-2801

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

1999

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.