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Impairment of stress granule assembly via inhibition of the eIF2alpha phosphorylation sensitizes glioma cells to chemotherapeutic agents

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Abstract

Malignant gliomas are a lethal type of brain tumors that poorly respond to chemotherapeutic drugs. Several therapy resistance mechanisms have been characterized. However, the response to stress through mRNA translational control has not been evaluated for this type of tumor. A potential target would involve the alpha subunit of eukaryotic translation initiation factor (eIF2α) that leads to assembly of stress granules (SG) which are cytoplasmic granules mainly composed by RNA binding proteins and untranslated mRNAs. We assessed whether glioma cells are capable of assembling SG after exposure to different classes of chemotherapeutic agents through evaluation of the effects of interfering in this process by impairing the eIF2α signaling. C6 and U87MG cells were exposed to bortezomib, cisplatin, or etoposide. Forced expression of a dominant negative mutant of eIF2α (eIF2αDN) was employed to block this pathway. We observed that exposure to drugs stimulated SG assembly. This was reduced in eIF2αDN-transfected cells and this strategy enhanced chemotherapeutically-induced cell death for all drugs. Our data suggest that SG assembly occurs in glioma cells in response to chemotherapeutic drugs in an eIF2α-dependent manner and this response is relevant for drug resistance. Interfering with eIF2α signaling pathway may be a potential strategy for new co-adjuvant therapies to treat gliomas.

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Acknowledgments

We would like to thank Dr. Fabíola M. Ribeiro for the assistance with the Floid Imaging System equipment and Mrs. Ilma M. Souza for technical support. FASVB, KML, JPV and LFFB hold a CAPES PhD Scholarship. AED hold a CAPES Master Scholarship. LSB, AMS, LPS, DAG and MMT hold CNPq Research Fellowships. This work was supported by Pró-Reitoria de Pesquisa da UFMG (PRPq-UFMG), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Pesquisa (CNPq) and Fundação de Amparo à Pesquisa do estado de Minas Gerais (FAPEMIG).

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Fabrício de Almeida Souza Vilas-Boas, Lucas Felipe Fernandes Bittencourt & Lucíola Silva Barcelos

  2. Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Aristóbolo Mendes da Silva

  3. Department of Clinical and Toxicological Analysis, Pharmacy Faculty, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Lirlândia Pires de Sousa, Kátia Maciel Lima & Juliana Priscila Vago

  4. Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Arthur Estanislau Dantas, Dawidson Assis Gomes & Mauro Martins Teixeira

  5. Department of Health Sciences, Federal University of Juiz de Fora—Advanced Campus, Governador Valadares, Minas Gerais, 35010-177, Brazil

    Márcia Carvalho Vilela

  6. Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas (ICB), Universidade Federal of Minas Gerais (UFMG), Av. Antônio Carlos, 6627, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Lucíola Silva Barcelos

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  1. Fabrício de Almeida Souza Vilas-Boas
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  2. Aristóbolo Mendes da Silva
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Correspondence to Lucíola Silva Barcelos.

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Vilas-Boas, F., da Silva, A.M., de Sousa, L.P. et al. Impairment of stress granule assembly via inhibition of the eIF2alpha phosphorylation sensitizes glioma cells to chemotherapeutic agents. J Neurooncol 127, 253–260 (2016). https://doi.org/10.1007/s11060-015-2043-3

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  • DOI: https://doi.org/10.1007/s11060-015-2043-3

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