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Comprehensive analysis of cytoskeleton regulatory genes identifies ezrin as a prognostic marker and molecular target in acute myeloid leukemia.
Lipreri da Silva, Jean Carlos; Coelho-Silva, Juan Luiz; Lima, Keli; Vicari, Hugo Passos; Lazarini, Mariana; Costa-Lotufo, Leticia Veras; Traina, Fabiola; Machado-Neto, João Agostinho.
Afiliação
  • Lipreri da Silva JC; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil.
  • Coelho-Silva JL; Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
  • Lima K; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil.
  • Vicari HP; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil.
  • Lazarini M; Department of Pharmaceutical Sciences, Federal University of São Paulo, Diadema, Brazil.
  • Costa-Lotufo LV; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil.
  • Traina F; Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
  • Machado-Neto JA; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil. jamachadoneto@usp.br.
Cell Oncol (Dordr) ; 44(5): 1105-1117, 2021 Oct.
Article em En | MEDLINE | ID: mdl-34196912
PURPOSE: Despite great advances that have been made in the understanding of the molecular complexity of acute myeloid leukemia (AML), very little has been translated into new therapies. Here, we set out to investigate the impact of cytoskeleton regulatory genes on clinical outcomes and their potential as therapeutic targets in AML. METHODS: Gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) AML study and used for survival and functional genomics analyses. For pharmacological tests, AML cells were exposed to ezrin (EZR) inhibitors and submitted to several cellular and molecular assays. RESULTS: High EZR expression was identified as an independent marker of worse outcomes in AML patients from the TCGA cohort (p < 0.05). Functional genomics analyses suggested that EZR contributes to responses to stimuli and signal transduction pathways in leukemia cells. EZR pharmacological inhibition with NSC305787 and NSC668394 reduced viability, proliferation, autonomous clonal growth, and cell cycle progression in AML cells (p < 0.05). NSC305787 had a greater potency and efficiency than NSC668394 in leukemia models. At the molecular level, EZR inhibitors reduced EZR, S6 ribosomal protein and 4EBP1 phosphorylation, and induced PARP1 cleavage in AML cells. NSC305787, but not NSC668394, favored a gene network involving cell cycle arrest and apoptosis in Kasumi 1 AML cells. CONCLUSIONS: From our data we conclude that EZR expression may serve as a prognostic factor in AML. Our preclinical findings indicate that ezrin inhibitors may be employed as a putative novel class of AML targeting drugs.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Citoesqueleto / Biomarcadores Tumorais / Leucemia Mieloide / Regulação Leucêmica da Expressão Gênica / Genes Reguladores / Proteínas do Citoesqueleto Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Adult / Female / Humans / Male Idioma: En Revista: Cell Oncol (Dordr) Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Citoesqueleto / Biomarcadores Tumorais / Leucemia Mieloide / Regulação Leucêmica da Expressão Gênica / Genes Reguladores / Proteínas do Citoesqueleto Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Adult / Female / Humans / Male Idioma: En Revista: Cell Oncol (Dordr) Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda