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Echinobase
ECB-ART-44232
Oncotarget 2015 Oct 06;630:29573-84. doi: 10.18632/oncotarget.4998.
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Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells.

Machado-Neto JA , de Melo Campos P , Favaro P , Lazarini M , da Silva Santos Duarte A , Lorand-Metze I , Costa FF , Saad ST , Traina F .


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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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Species referenced: Echinodermata
Genes referenced: LOC100888693 LOC100893907 LOC115919910 LOC115921826 LOC576433 LOC579431 LOC590297 LOC590852 parp1 tubgcp2


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References [+] :
Baxter, Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. 2005, Pubmed