Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-39822
Archer, C R; Koomoa, D L T; Mitsunaga, E M; Clerc, J; Shimizu, M; Kaiser, M; Schellenberg, B; Dudler, R; Bachmann, A S (2010). Syrbactin class proteasome inhibitor-induced apoptosis and autophagy occurs in association with p53 accumulation and Akt/PKB activation in neuroblastoma. Biochemical Pharmacology, 80(2):170-178.
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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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||07 Faculty of Science > Institute of Plant Biology|
|DDC:||580 Plants (Botany)|
|Date:||15 July 2010|
|Deposited On:||20 Jan 2011 08:52|
|Last Modified:||28 Nov 2013 02:04|
|Additional Information:||aM eingefordert 20.1.11 kw|
|Citations:||Web of Science®. Times Cited: 18|
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