Toxic effects of phytol and retinol on human glioblastoma cells are associated with modulation of cholesterol and fatty acid biosynthetic pathways

Autor(es)

Facchini, Gustavo ^[1] ; Ignarro, Raffaela Silvestre ^[1] ; Rodrigues-Silva, Erika ^[2] ; Vieira, Andre Schwambach ^[3] ; Lopes-Cendes, Iscia ^[4] ; Castilho, Roger Frigerio ^[2] ; Rogerio, Fabio ^[1]

Afiliação do(s) autor(es)

^[1] State Univ Campinas UNICAMP, Dept Anat Pathol, Fac Med Sci, Ave Tessalia Vieira de Camargo 126, BR-13083887 Campinas, SP - Brazil

^[2] State Univ Campinas UNICAMP, Dept Clin Pathol, Fac Med Sci, Ave Tessalia Vieira de Camargo 126, BR-13083887 Campinas, SP - Brazil

^[3] State Univ Campinas UNICAMP, Inst Biol, Dept Struct & Funct Biol, R Monteiro Lobato 255, BR-13083862 Campinas, SP - Brazil

^[4] State Univ Campinas UNICAMP, Dept Med Genet, Fac Med Sci, Ave Tessalia Vieira de Camargo 126, BR-13083887 Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF NEURO-ONCOLOGY; v. 136, n. 3, p. 435-443, FEB 2018.
• Citações Web of Science: 4

Resumo

Glioblastoma (GBM) is the most common primary brain tumor. Genetic mutations may reprogram the metabolism of neoplastic cells. Particularly, alterations in cholesterol and fatty acid biosynthetic pathways may favor biomass synthesis and resistance to therapy. Therefore, compounds that interfere with those pathways, such as phytol (PHY) and retinol (RET), may be appropriate for cytotoxic approaches. We tested the effect of PHY or RET on the viability of human GBM cell lines (U87MG, A172 and T98G). Since the compounds showed a dose-dependent cytotoxic effect, additional analyses were performed with IC50 values. Transcriptome analyses of A172 cells treated with PHY IC50 or RET IC50 revealed down-regulated genes involved in cholesterol and/or fatty acid biosynthetic pathways. Thus, we investigated the expression of proteins required for cholesterol and/or fatty acid synthesis after treating all lineages with PHY IC50 or RET IC50 and comparing them with controls. Sterol regulatory element-binding protein 1 (SREBP-1) expression was reduced by PHY in U87 and T98G cells. However, fatty acid synthase (FAS) protein expression, which is regulated by SREBP-1, was down-regulated in all lineages after both treatments. Moreover, farnesyl-diphosphate farnesyltransferase (FDFT1) levels, a protein associated with cholesterol synthesis, were reduced in all lineages by PHY and in U87MG and A172 cells by RET. Our results suggest that SREBP-1, FAS and FDFT1 are potential target(s) for future in vivo approaches against GBM and support the use of inhibitors of their synthesis, including PHY and RET, for such approaches. (AU)

• Processo FAPESP: 11/50400-0 - Metabolismo energético, estado redox e funcionalidade mitocondrial na morte celular e em desordens cardiometabólicas e neurodegenerativas
• Beneficiário: Aníbal Eugênio Vercesi
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/07559-3 - Instituto Brasileiro de Neurociência e Neurotecnologia - BRAINN
• Beneficiário: Fernando Cendes
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 13/02618-1 - Análise do estresse oxidativo induzido por sulfasalazina associado com a ação do quimioterápico temozolomida em células de glioma humano e de rato
• Beneficiário: Fábio Rogério
• Modalidade de apoio: Auxílio à Pesquisa - Regular