| Texto completo | |
| Autor(es): |
Machado-Neto, Joao Agostinho
[1, 2]
;
Coelho-Silva, Juan Luiz
[2]
;
de Souza Santos, Fabio Pires
[3, 4]
;
Scheucher, Priscila Santos
[2]
;
Campregher, Paulo Vidal
[3, 4]
;
Hamerschlak, Nelson
[3]
;
Rego, Eduardo Magalhaes
[2]
;
Traina, Fabiola
[2]
Número total de Autores: 8
|
| Afiliação do(s) autor(es): | [1] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo - Brazil
[2] Univ Sao Paulo, Dept Med Images Hematol & Clin Oncol, Ribeirao Preto Med Sch, Av Bandeirante, BR-3900 Ribeirao Preto, SP - Brazil
[3] Hosp Israelita Albert Einstein Sao Paulo, Ctr Oncol & Hematol Familia Dayan Daycoval, Sao Paulo - Brazil
[4] Hosp Israelita Albert Einstein Sao Paulo, Inst Ensino & Pesquisa, Sao Paulo - Brazil
Número total de Afiliações: 4
|
| Tipo de documento: | Artigo Científico |
| Fonte: | INVESTIGATIONAL NEW DRUGS; v. 38, n. 3, p. 733-745, JUN 2020. |
| Citações Web of Science: | 0 |
| Resumo | |
JAK2(V617F) can mimic growth factor signaling, leading to PI3K/AKT/mTOR activation and inhibition of autophagy. We hypothesized that selective inhibition of JAK1/2 by ruxolitinib could induce autophagy and limit drug efficacy in myeloproliferative neoplasms (MPN). Therefore, we investigated the effects of ruxolitinib treatment on autophagy-related genes and cellular processes, to determine the potential benefit of autophagy inhibitors plus ruxolitinib in JAK2(V617F) cells, and to verify the frequency and clinical impact of autophagy-related gene mutations in patients with MPNs. In SET2 JAK2(V617F) cells, ruxolitinib treatment induced autophagy and modulated 26 out of 79 autophagy-related genes. Ruxolitinib treatment reduced the expressions of important autophagy regulators, including mTOR/p70S6K/4EBP1 and the STAT/BCL2 axis, in a dose- and time-dependent manner. Pharmacological inhibition of autophagy was able to significantly suppress ruxolitinib-induced autophagy and increased ruxolitinib-induced apoptosis. Mutations in autophagy-related genes were found in 15.5% of MPN patients and were associated with increased age and a trend towards worse survival. In conclusion, ruxolitinib induces autophagy in JAK2(V617F) cells, potentially by modulation of mTOR-, STAT- and BCL2-mediated signaling. This may lead to inhibition of apoptosis. Our results suggest that the combination of ruxolitinib with pharmacological inhibitors of autophagy, such as chloroquine, may be a promising strategy to treat patients with JAK2(V617F)-mutated MPNs. (AU) | |
| Processo FAPESP: | 14/50947-7 - INCT 2014: em Células Tronco e Terapia Celular no Câncer |
| Beneficiário: | Dimas Tadeu Covas |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |
| Processo FAPESP: | 14/23092-0 - Investigação da função da proteína IRS2 em células hematopoéticas |
| Beneficiário: | João Agostinho Machado Neto |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 17/19864-6 - Investigação da participação das proteínas IRS1 e IRS2 na hematopoese normal e síndrome mielodisplásica utilizando modelos murinos e células-tronco hematopoéticas humanas |
| Beneficiário: | Fabíola Traina |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 13/08135-2 - CTC - Centro de Terapia Celular |
| Beneficiário: | Dimas Tadeu Covas |
| Modalidade de apoio: | Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs |