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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2(V617F) cells

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Autor(es):
Machado-Neto, Joao Agostinho [1] ; Campos, Paula de Melo [1] ; Favaro, Patricia [1] ; Lazarini, Mariana [1] ; Santos Duarte, Adriana da Silva [1] ; Lorand-Metze, Irene [1] ; Costa, Fernando Ferreira [1] ; Olalla Saad, Sara Teresinha [1] ; Traina, Fabiola [1]
Número total de Autores: 9
Afiliação do(s) autor(es):
[1] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, Hemoctr Unicamp, Inst Nacl Ciencia & Tecnol Sangue, Sao Paulo - Brazil
Número total de Afiliações: 1
Tipo de documento: Artigo Científico
Fonte: ONCOTARGET; v. 6, n. 30, p. 29573-29584, OCT 6 2015.
Citações Web of Science: 7
Resumo

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. (AU)

Processo FAPESP: 12/09982-8 - Investigação de alterações moleculares em neoplasias mielóides
Beneficiário:Fabíola Traina
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 14/23092-0 - Investigação da função da proteína IRS2 em células hematopoéticas
Beneficiário:João Agostinho Machado Neto
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 11/06840-5 - Estudo da função de ANKHD1 na proliferação, apoptose e ciclo celular em neoplasias hematológicas
Beneficiário:João Agostinho Machado Neto
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 11/51959-0 - Biologia das doenças neoplásicas da medula óssea
Beneficiário:Sara Teresinha Olalla Saad
Linha de fomento: Auxílio à Pesquisa - Temático