Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death.
BMC Cancer
; 10: 526, 2010 Oct 04.
Article
em En
| MEDLINE
| ID: mdl-20920357
ABSTRACT
BACKGROUND:
Glycogen Synthase Kinase-3 (GSK-3) α and ß are two serine-threonine kinases controlling insulin, Wnt/ß-catenin, NF-κB signaling and other cancer-associated transduction pathways. Recent evidence suggests that GSK-3 could function as growth-promoting kinases, especially in malignant cells. In this study, we have investigated GSK-3α and GSK-3ß function in multiple myeloma (MM).METHODS:
GSK-3 α and ß expression and cellular localization were investigated by Western blot (WB) and immunofluorescence analysis in a panel of MM cell lines and in freshly isolated plasma cells from patients. MM cell growth, viability and sensitivity to bortezomib was assessed upon treatment with GSK-3 specific inhibitors or transfection with siRNAs against GSK-3 α and ß isoforms. Survival signaling pathways were studied with WB analysis.RESULTS:
GSK-3α and GSK-3ß were differently expressed and phosphorylated in MM cells. Inhibition of GSK-3 with the ATP-competitive, small chemical compounds SB216763 and SB415286 caused MM cell growth arrest and apoptosis through the activation of the intrinsic pathway. Importantly, the two inhibitors augmented the bortezomib-induced MM cell cytotoxicity. RNA interference experiments showed that the two GSK-3 isoforms have distinct roles GSK-3ß knock down decreased MM cell viability, while GSK-3α knock down was associated with a higher rate of bortezomib-induced cytotoxicity. GSK-3 inhibition caused accumulation of ß-catenin and nuclear phospho-ERK1, 2. Moreover, GSK-3 inhibition and GSK-3α knockdown enhanced bortezomib-induced AKT and MCL-1 protein degradation. Interestingly, bortezomib caused a reduction of GSK-3 serine phosphorylation and its nuclear accumulation with a mechanism that resulted partly dependent on GSK-3 itself.CONCLUSIONS:
These data suggest that in MM cells GSK-3α and ß i) play distinct roles in cell survival and ii) modulate the sensitivity to proteasome inhibitors.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Pirazinas
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Ácidos Borônicos
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Regulação da Expressão Gênica
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Quinase 3 da Glicogênio Sintase
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Mieloma Múltiplo
Limite:
Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article