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Syrbactin class proteasome inhibitor-induced apoptosis and autophagy occurs in association with p53 accumulation and Akt/PKB activation in neuroblastoma.

Abstract
Syrbactins belong to a new class of proteasome inhibitors which include syringolins and glidobactins. These small molecules are structurally distinct from other, well-established proteasome inhibitors, and bind the eukaryotic 20S proteasome by a novel mechanism. In this study, we examined the effects of syringolin A (SylA) and glidobactin A (GlbA) as well as two synthetic SylA-analogs (SylA-PEG and SylA-LIP) in human neuroblastoma (SK-N-SH), human multiple myeloma (MM1.S, MM1.RL, and U266), and human ovarian cancer (SKOV-3) cells. While all four syrbactins inhibited cell proliferation in a dose-dependent manner, GlbA was most potent in both dexamethasone-sensitive MM1.S cells (IC(50): 0.004microM) and dexamethasone-resistant MM1.RL cells (IC(50): 0.005microM). Syrbactins also inhibited the chymotrypsin-like proteasome activity in a dose-dependent fashion, and GlbA was most effective in SK-N-SH cells (IC(50): 0.015microM). The GlbA-promoted inhibition of proteasomal activity in SK-N-SH cells resulted in the accumulation of ubiquitinated proteins and tumor suppressor protein p53 and led to apoptotic cell death in a time-dependent manner. GlbA treatment also promoted the activation of Akt/PKB via phosphorylation at residue Ser(473) and induced autophagy as judged by the presence of the lipidated form of microtubule-associated protein 1 light chain 3 (LC3) and autophagosomes. Collectively, our data suggest that syrbactins belong to a new and effective proteasome inhibitor class which promotes cell death. Proteasome inhibition is a promising strategy for targeted anticancer therapy and syrbactins are a new class of inhibitors which provide a structural platform for the development of novel, proteasome inhibitor-based drug therapeutics.
AuthorsCrystal R Archer, Dana-Lynn T Koomoa, Erin M Mitsunaga, Jérôme Clerc, Mariko Shimizu, Markus Kaiser, Barbara Schellenberg, Robert Dudler, André S Bachmann
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 80 Issue 2 Pg. 170-8 (Jul 15 2010) ISSN: 1873-2968 [Electronic] England
PMID20362557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright2010 Elsevier Inc. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Peptides, Cyclic
  • Protease Inhibitors
  • Tumor Suppressor Protein p53
  • syringolin A
  • glidobactin A
  • Proto-Oncogene Proteins c-akt
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Autophagy (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Infant
  • Male
  • Multiple Myeloma (drug therapy, metabolism, pathology)
  • Neuroblastoma (drug therapy, metabolism, pathology)
  • Ovarian Neoplasms (drug therapy, metabolism, pathology)
  • Peptides, Cyclic (pharmacology)
  • Protease Inhibitors (pharmacology)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Tumor Suppressor Protein p53 (metabolism)

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