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Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells.
Oncotarget 2015; 6(30):29573-84O

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.

Authors+Show Affiliations

Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. Current address: Department of Biological Sciences, Federal University of São Paulo, Diadema, São Paulo, Brazil.Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. Current address: Department of Biological Sciences, Federal University of São Paulo, Diadema, São Paulo, Brazil.Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. Current address: Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26356819

Citation

Machado-Neto, João Agostinho, et al. "Stathmin 1 Inhibition Amplifies Ruxolitinib-induced Apoptosis in JAK2V617F Cells." Oncotarget, vol. 6, no. 30, 2015, pp. 29573-84.
Machado-Neto JA, de Melo Campos P, Favaro P, et al. Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells. Oncotarget. 2015;6(30):29573-84.
Machado-Neto, J. A., de Melo Campos, P., Favaro, P., Lazarini, M., da Silva Santos Duarte, A., Lorand-Metze, I., ... Traina, F. (2015). Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells. Oncotarget, 6(30), pp. 29573-84. doi:10.18632/oncotarget.4998.
Machado-Neto JA, et al. Stathmin 1 Inhibition Amplifies Ruxolitinib-induced Apoptosis in JAK2V617F Cells. Oncotarget. 2015 Oct 6;6(30):29573-84. PubMed PMID: 26356819.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells. AU - Machado-Neto,João Agostinho, AU - de Melo Campos,Paula, AU - Favaro,Patricia, AU - Lazarini,Mariana, AU - da Silva Santos Duarte,Adriana, AU - Lorand-Metze,Irene, AU - Costa,Fernando Ferreira, AU - Saad,Sara Teresinha Olalla, AU - Traina,Fabiola, PY - 2015/02/27/received PY - 2015/08/11/accepted PY - 2015/9/11/entrez PY - 2015/9/12/pubmed PY - 2016/8/3/medline KW - STAT3 KW - Stathmin 1 KW - myeloproliferative neoplasms KW - paclitaxel KW - ruxolitinib SP - 29573 EP - 84 JF - Oncotarget JO - Oncotarget VL - 6 IS - 30 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/26356819/Stathmin_1_inhibition_amplifies_ruxolitinib_induced_apoptosis_in_JAK2V617F_cells_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=4998 DB - PRIME DP - Unbound Medicine ER -