Identification and characterization of a novel proteasome inhibitor with apoptotic properties in neuroblastoma

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3258 Pathogenic bacteria often use effector molecules to increase virulence. In most cases, the mode of action of effectors remains unknown. In this work, we identified a novel molecule (SylA) produced by a plant pathogen that acts as a virulence factor and inhibits all three catalytic activities of the eukaryotic proteasome ( in vitro and in vivo ), thus adding proteasome inhibition to the repertoire of modes of action of virulence factors. Co-crystallization of SylA with the yeast proteasome revealed a novel mechanism of covalent binding to the catalytic subunits. Our data further show that SylA modulates the protein signaling network of neuroblastoma cells and induces apoptosis. Proteasome inhibitors are a promising new class of anti-cancer drugs as evidenced by bortezomib, a FDA-approved drug for the treatment of multiple myeloma. Intriguingly, SylA is a natural product molecule with unique structural features that irreversibly inhibits proteasomal activity by a novel mechanism, thus representing a new structural class of proteasome inhibitors with great potential for further development into an effective anti-cancer drug.