Reversine exhibits antineoplastic activity in JAK2(V)(617)(F)-positive myeloproliferative neoplasms

Autor(es)

Lima, Keli ^[1] ; Elias Godoy Carlos, Jorge Antonio ^[1] ; Alves-Paiva, Raquel de Melo ^[2] ; Vicari, Hugo Passos ^[1] ; de Souza Santos, Fabio Pires ^[2] ; Hamerschlak, Nelson ^[2] ; Costa-Lotufo, Leticia Veras ^[1] ; Traina, Fabiola ^[3] ; Machado-Neto, Joao Agostinho ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Biomed Sci Inst, Dept Pharmacol, Sao Paulo - Brazil

^[2] Albert Einstein Hosp, Einsteins Teaching & Res Inst, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Med Images Hematol & Clin Oncol, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 9, JUL 9 2019.
• Citações Web of Science: 0

Resumo

JAK2/STAT signaling participates in the Ph-negative myeloproliferative neoplasms (MPN) pathophysiology and has been targeted by ruxolitinib, a JAK1/2 inhibitor. In the present study, the impact of ruxolitinib treatment on cytoskeleton-related genes expression was explored. In SET2 cells, AURKA and AURKB expression/activity were downregulated in a dose- and time-dependent manner by ruxolitinib. Reversine, a multikinase inhibitor selective for aurora kinases, reduced cell viability in a dose- and/or time-dependent manner in JAK2(V)(617)F cells. Reversine significantly increased apoptosis and mitotic catastrophe, and reduced cell proliferation and clonogenic capacity in SET2 and HEL cells. In the molecular scenario, reversine induced DNA damage and apoptosis markers, as well as, reduced AURKA and AURKB expression/activity. In SET2 cells, reversine modulated the expression of 32 out of 84 apoptosis-related genes investigated, including downregulation of antiapoptotic (BCL2, BCL2L1, and BIRC5) and upregulation of proapoptotic (BIK, BINP3, and BNIP3L) genes. Synergism experiments indicated that low dose of reversine had a potentiating effect under ruxolitinib treatment at low doses in SET2 cells. In summary, our exploratory study establishes new targets, related to the regulation of the cellular cytoskeleton, for potential pharmacological intervention in MPN. These findings indicate that AURKA and AURKB participate in the JAK2/STAT signaling pathway and contribute to the MPN phenotype. (AU)

• Processo FAPESP: 17/24993-0 - Investigação da participação de Stathmin 1 e da instabilidade dos microtúbulos no fenótipo de neoplasias hematológicas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular