Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells.
Oncotarget
; 6(30): 29573-84, 2015 Oct 06.
Article
en En
| MEDLINE
| ID: mdl-26356819
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Apoptosis
/
Estatmina
/
Janus Quinasa 2
Límite:
Adult
/
Aged
/
Aged80
/
Humans
/
Middle aged
Idioma:
En
Revista:
Oncotarget
Año:
2015
Tipo del documento:
Article
País de afiliación:
Brasil
Pais de publicación:
Estados Unidos