Produção Nacional
Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells
2015; Impact Journals LLC; Volume: 6; Issue: 30 Linguagem: Inglês
10.18632/oncotarget.4998
ISSN1949-2553
AutoresJoão Agostinho Machado‐Neto, Paula de Melo Campos, Patrícia Favaro, Mariana Lazarini, Adriana da Silva Santos Duarte, Irene Lorand‐Metze, Fernando Ferreira Costa, Sara Teresinha Olalla Saad, Fabı́ola Traina,
Tópico(s)Kruppel-like factors research
Resumo// João Agostinho Machado-Neto 1 , Paula de Melo Campos 1 , Patricia Favaro 1, 2 , Mariana Lazarini 1, 2 , Adriana da Silva Santos Duarte 1 , Irene Lorand-Metze 1 , Fernando Ferreira Costa 1 , Sara Teresinha Olalla Saad 1 , Fabiola Traina 1, 3 1 Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil 2 Current address: Department of Biological Sciences, Federal University of São Paulo, Diadema, São Paulo, Brazil 3 Current address: Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil Correspondence to: Fabiola Traina, e-mail: ftraina@fmrp.usp.br ; e-mail: fabiolatraina@gmail.com Keywords: myeloproliferative neoplasms, STAT3, stathmin 1, ruxolitinib, paclitaxel Received: February 27, 2015 Accepted: August 11, 2015 Published: August 24, 2015 ABSTRACT The JAK/STAT pathway is constitutively activated in myeloproliferative neoplasms and can be inhibited by ruxolitinib, a selective JAK1/2 inhibitor. The JAK2 V617F mutation leads to constitutive STAT3 phosphorylation and potentially leads to inhibition of Stathmin 1 activity via STAT3. In support of this hypothesis, we found that, in HEL JAK2 V617F cells, ruxolitinib treatment decreased STAT3 and Stathmin 1 association, induced Stathmin 1 activation and microtubule instability. Silencing of Stathmin 1 significantly reduced cell proliferation and clonal growth, and increased apoptosis induced by ruxolitinib. Stathmin 1 silencing also prevented ruxolitinib-induced microtubule instability. To phenocopy the effect of Stathmin 1 inhibition, cells were treated with paclitaxel, a microtubule-stabilizing drug, in association or not with ruxolitinib; combined treatment significantly increased apoptosis, when compared to monotherapy. Notably, Stathmin 1 mRNA levels were highly expressed in CD34 + cells from primary myelofibrosis patients. We then proposed that an undesired effect of ruxolitinib treatment may constitute Stathmin 1 activation and microtubule instability in JAK2 V617F cells. Induction of microtubule stability, through Stathmin 1 silencing or paclitaxel treatment, combined with ruxolitinib could be an effective strategy for promoting apoptosis in JAK2 V617F cells.
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