Syrbactin class proteasome inhibitor-induced apoptosis and autophagy occurs in association with p53 accumulation and Akt/PKB activation in neuroblastoma.
Biochem Pharmacol
; 80(2): 170-8, 2010 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-20362557
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Inhibidores de Proteasas
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Autofagia
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Proteína p53 Supresora de Tumor
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Apoptosis
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Proteínas Proto-Oncogénicas c-akt
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Neuroblastoma
Tipo de estudio:
Risk_factors_studies
Límite:
Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Biochem Pharmacol
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos