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Open Access Highly Accessed Research article

Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death

Francesco Piazza12, Sabrina Manni12, Laura Quotti Tubi12, Barbara Montini12, Laura Pavan12, Anna Colpo12, Marianna Gnoato12, Anna Cabrelle12, Fausto Adami1, Renato Zambello12, Livio Trentin12, Carmela Gurrieri12 and Gianpietro Semenzato12*

Author Affiliations

1 Department of Clinical and Experimental Medicine, Hematology and Clinical Immunology Branch, University of Padua School of Medicine, Via Giustiniani 2 -35128-Padua, Italy

2 Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica, Fondazione per la Ricerca Biomedica Avanzata, Via Orus 2 - 35129 - Padua, Italy

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BMC Cancer 2010, 10:526  doi:10.1186/1471-2407-10-526

Published: 4 October 2010

Abstract

Background

Glycogen Synthase Kinase-3 (GSK-3) α and β are two serine-threonine kinases controlling insulin, Wnt/β-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-3β function in multiple myeloma (MM).

Methods

GSK-3 α and β 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 β isoforms. Survival signaling pathways were studied with WB analysis.

Results

GSK-3α and GSK-3β 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-3β 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 β-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 β i) play distinct roles in cell survival and ii) modulate the sensitivity to proteasome inhibitors.