Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2(V617F) cells

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: INVESTIGATIONAL NEW DRUGS; v. 38, n. 3, p. 733-745, JUN 2020.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 14/50947-7 - INCT 2014: in Stem Cell and Cell Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/23092-0 - Investigation of IRS2 protein function in hematopoietic cells
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/19864-6 - Investigation of IRS1 and IRS2 function in normal hematopoiesis and myelodysplastic syndrome using murine models and human hematopoietic stem cells
• Grantee: Fabíola Traina
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC