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Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2V617F cells.
Invest New Drugs. 2020 06; 38(3):733-745.IN

Abstract

JAK2V617F 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 JAK2V617F cells, and to verify the frequency and clinical impact of autophagy-related gene mutations in patients with MPNs. In SET2 JAK2V617F 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 JAK2V617F 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 JAK2V617F-mutated MPNs.

Authors+Show Affiliations

Department of Medical Images, Hematology and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Av. Bandeirante, Ribeirão Preto, SP, 3900, Brazil. Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil.Department of Medical Images, Hematology and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Av. Bandeirante, Ribeirão Preto, SP, 3900, Brazil.Centro de Oncologia e Hematologia Familia Dayan-Daycoval, Hospital Israelita Albert Einstein São Paulo, São Paulo, Brazil. Instituto de Ensino e Pesquisa, Hospital Israelita Albert Einstein São Paulo, São Paulo, Brazil.Department of Medical Images, Hematology and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Av. Bandeirante, Ribeirão Preto, SP, 3900, Brazil.Centro de Oncologia e Hematologia Familia Dayan-Daycoval, Hospital Israelita Albert Einstein São Paulo, São Paulo, Brazil. Instituto de Ensino e Pesquisa, Hospital Israelita Albert Einstein São Paulo, São Paulo, Brazil.Centro de Oncologia e Hematologia Familia Dayan-Daycoval, Hospital Israelita Albert Einstein São Paulo, São Paulo, Brazil.Department of Medical Images, Hematology and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Av. Bandeirante, Ribeirão Preto, SP, 3900, Brazil.Department of Medical Images, Hematology and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Av. Bandeirante, Ribeirão Preto, SP, 3900, Brazil. ftraina@fmrp.usp.br.

Pub Type(s)

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

Language

eng

PubMed ID

31286322

Citation

Machado-Neto, João Agostinho, et al. "Autophagy Inhibition Potentiates Ruxolitinib-induced Apoptosis in JAK2V617F Cells." Investigational New Drugs, vol. 38, no. 3, 2020, pp. 733-745.
Machado-Neto JA, Coelho-Silva JL, Santos FPS, et al. Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2V617F cells. Invest New Drugs. 2020;38(3):733-745.
Machado-Neto, J. A., Coelho-Silva, J. L., Santos, F. P. S., Scheucher, P. S., Campregher, P. V., Hamerschlak, N., Rego, E. M., & Traina, F. (2020). Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2V617F cells. Investigational New Drugs, 38(3), 733-745. https://doi.org/10.1007/s10637-019-00812-5
Machado-Neto JA, et al. Autophagy Inhibition Potentiates Ruxolitinib-induced Apoptosis in JAK2V617F Cells. Invest New Drugs. 2020;38(3):733-745. PubMed PMID: 31286322.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2V617F cells. AU - Machado-Neto,João Agostinho, AU - Coelho-Silva,Juan Luiz, AU - Santos,Fábio Pires de Souza, AU - Scheucher,Priscila Santos, AU - Campregher,Paulo Vidal, AU - Hamerschlak,Nelson, AU - Rego,Eduardo Magalhães, AU - Traina,Fabiola, Y1 - 2019/07/08/ PY - 2019/04/08/received PY - 2019/06/06/accepted PY - 2019/7/10/pubmed PY - 2019/7/10/medline PY - 2019/7/10/entrez KW - Apoptosis KW - Autophagy KW - Chloroquine KW - Myeloproliferative neoplasms KW - Ruxolitinib SP - 733 EP - 745 JF - Investigational new drugs JO - Invest New Drugs VL - 38 IS - 3 N2 - JAK2V617F 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 JAK2V617F cells, and to verify the frequency and clinical impact of autophagy-related gene mutations in patients with MPNs. In SET2 JAK2V617F 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 JAK2V617F 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 JAK2V617F-mutated MPNs. SN - 1573-0646 UR - https://www.unboundmedicine.com/medline/citation/31286322/Autophagy_inhibition_potentiates_ruxolitinib_induced_apoptosis_in_JAK2V617F_cells_ L2 - https://doi.org/10.1007/s10637-019-00812-5 DB - PRIME DP - Unbound Medicine ER -
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