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

被引：37

作者：

Piazza, Francesco ^{[1
,2
]}

Manni, Sabrina ^{[1
,2
]}

Tubi, Laura Quotti ^{[1
,2
]}

Montini, Barbara ^{[1
,2
]}

Pavan, Laura ^{[1
,2
]}

Colpo, Anna ^{[1
,2
]}

Gnoato, Marianna ^{[1
,2
]}

Cabrelle, Anna ^{[1
,2
]}

Adami, Fausto ^{[1
]}

Zambello, Renato ^{[1
,2
]}

Trentin, Livio ^{[1
,2
]}

Gurrieri, Carmela ^{[1
,2
]}

Semenzato, Gianpietro ^{[1
,2
]}

机构：

[1] Univ Padua, Sch Med, Dept Clin & Expt Med, Hematol & Clin Immunol Branch, I-35128 Padua, Italy

[2] Fdn Ric Biomed Avanzata, Ctr Eccellenza Ric Biomed, Venetian Inst Mol Med, I-35129 Padua, Italy

来源：

BMC CANCER | 2010年 / 10卷

关键词：

NF-KAPPA-B; NUCLEAR ACCUMULATION; PANCREATIC-CANCER; INDUCED APOPTOSIS; DOWN-REGULATION; BONE-MARROW; STEM-CELLS; ACTIVATION; INHIBITION; PROLIFERATION;

D O I：

10.1186/1471-2407-10-526

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Glycogen Synthase Kinase-3 (GSK-3) alpha and beta are two serine-threonine kinases controlling insulin, Wnt/beta-catenin, NF-kappa B 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-3 alpha and GSK-3 beta function in multiple myeloma (MM). Methods: GSK-3 alpha and beta 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 alpha and beta isoforms. Survival signaling pathways were studied with WB analysis. Results: GSK-3 alpha and GSK-3 beta 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-3 beta knock down decreased MM cell viability, while GSK-3 alpha knock down was associated with a higher rate of bortezomib-induced cytotoxicity. GSK-3 inhibition caused accumulation of beta-catenin and nuclear phospho-ERK1, 2. Moreover, GSK-3 inhibition and GSK-3 alpha 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-3 alpha and beta i) play distinct roles in cell survival and ii) modulate the sensitivity to proteasome inhibitors.

引用

页数：14