Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-10-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/10/526 |
| _version_ | 1818563059399000064 |
|---|---|
| author | Colpo Anna Pavan Laura Montini Barbara Tubi Laura Manni Sabrina Piazza Francesco Gnoato Marianna Cabrelle Anna Adami Fausto Zambello Renato Trentin Livio Gurrieri Carmela Semenzato Gianpietro |
| author_facet | Colpo Anna Pavan Laura Montini Barbara Tubi Laura Manni Sabrina Piazza Francesco Gnoato Marianna Cabrelle Anna Adami Fausto Zambello Renato Trentin Livio Gurrieri Carmela Semenzato Gianpietro |
| author_sort | Colpo Anna |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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).</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p> |
| first_indexed | 2024-12-14T01:11:54Z |
| format | Article |
| id | doaj.art-5d287dde92334271baf37c271009839e |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-14T01:11:54Z |
| publishDate | 2010-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-5d287dde92334271baf37c271009839e2022-12-21T23:22:43ZengBMCBMC Cancer1471-24072010-10-0110152610.1186/1471-2407-10-526Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell deathColpo AnnaPavan LauraMontini BarbaraTubi LauraManni SabrinaPiazza FrancescoGnoato MariannaCabrelle AnnaAdami FaustoZambello RenatoTrentin LivioGurrieri CarmelaSemenzato Gianpietro<p>Abstract</p> <p>Background</p> <p>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).</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p>http://www.biomedcentral.com/1471-2407/10/526 |
| spellingShingle | Colpo Anna Pavan Laura Montini Barbara Tubi Laura Manni Sabrina Piazza Francesco Gnoato Marianna Cabrelle Anna Adami Fausto Zambello Renato Trentin Livio Gurrieri Carmela Semenzato Gianpietro Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death BMC Cancer |
| title | Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death |
| title_full | Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death |
| title_fullStr | Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death |
| title_full_unstemmed | Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death |
| title_short | Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death |
| title_sort | glycogen synthase kinase 3 regulates multiple myeloma cell growth and bortezomib induced cell death |
| url | http://www.biomedcentral.com/1471-2407/10/526 |
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