Oncotarget

Research Papers:

Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells

João Agostinho Machado-Neto _, Paula de Melo Campos, Patricia Favaro, Mariana Lazarini, Adriana da Silva Santos Duarte, Irene Lorand-Metze, Fernando Ferreira Costa, Sara Teresinha Olalla Saad and Fabiola Traina

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:29573-29584. https://doi.org/10.18632/oncotarget.4998

Metrics: PDF 836 views  |   HTML 1043 views  |   ?  


Abstract

João Agostinho Machado-Neto1, Paula de Melo Campos1, Patricia Favaro1,2, Mariana Lazarini1,2, Adriana da Silva Santos Duarte1, Irene Lorand-Metze1, Fernando Ferreira Costa1, Sara Teresinha Olalla Saad1, Fabiola Traina1,3

1Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil

2Current address: Department of Biological Sciences, Federal University of São Paulo, Diadema, São Paulo, Brazil

3Current 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 JAK2V617F 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 JAK2V617F 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 JAK2V617F cells. Induction of microtubule stability, through Stathmin 1 silencing or paclitaxel treatment, combined with ruxolitinib could be an effective strategy for promoting apoptosis in JAK2V617F cells.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 4998