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

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]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, Hemoctr Unicamp, Inst Nacl Ciencia & Tecnol Sangue, Sao Paulo - Brazil

• 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: 11/51959-0 - Biologia das doenças neoplásicas da medula óssea
• Beneficiário: Sara Teresinha Olalla Saad
• Linha de fomento: Auxílio à Pesquisa - Temático
• 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: 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: 12/09982-8 - Investigação de alterações moleculares em neoplasias mieloides.
• Beneficiário: Fabíola Traina
• Linha de fomento: Auxílio à Pesquisa - Regular