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

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Abstract

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.

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Funding

This work was supported by grants from FAPESP (2011/50400-0; 2013/02618-1; 2013/07559-3) and FAEPEX/UNICAMP (379/13; 554/14; 621/14).

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Author notes

  1. Gustavo Facchini and Raffaela Silvestre Ignarro authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Av. Tessália Vieira de Camargo, 126, Campinas, SP, Zip Code: 13083-887, Brazil

    Gustavo Facchini, Raffaela Silvestre Ignarro & Fabio Rogerio

  2. Department of Clinical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Av. Tessália Vieira de Camargo, 126, Campinas, SP, Zip Code: 13083-887, Brazil

    Erika Rodrigues-Silva & Roger Frigério Castilho

  3. Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), R. Monteiro Lobato, 255, Campinas, SP, Zip Code: 13083-862, Brazil

    André Schwambach Vieira

  4. Department of Medical Genetics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Av. Tessália Vieira de Camargo, 126, Campinas, SP, Zip Code: 13083-887, Brazil

    Iscia Lopes-Cendes

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  1. Gustavo Facchini
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Correspondence to Fabio Rogerio.

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11060_2017_2672_MOESM1_ESM.xls

Online Resource 1. Gene expression data in human glioblastoma A172 cells after 72 hours of treatment with PHY IC50 or RET IC50. Columns in Tables 1-2 show gene symbols, log2fold changes relative to DMEM with 0.1% DMSO treated cells, p-values and adjusted p-values. Tables 3-6 contain enriched pathways for up- and down-regulated genes for each group. (XLS 4698 KB)

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Facchini, G., Ignarro, R.S., Rodrigues-Silva, E. et al. Toxic effects of phytol and retinol on human glioblastoma cells are associated with modulation of cholesterol and fatty acid biosynthetic pathways. J Neurooncol 136, 435–443 (2018). https://doi.org/10.1007/s11060-017-2672-9

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  • DOI: https://doi.org/10.1007/s11060-017-2672-9

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