title: Impairment of stress granule assembly via inhibition of the eIF2alpha phosphorylation sensitizes glioma cells to chemotherapeutic agents.
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 (eIF2α(DN)) was employed to block this pathway. We observed that exposure to drugs stimulated SG assembly. This was reduced in eIF2α(DN)-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.
authors.affiliation: Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Fabrício de Almeida Souza
authors.initials: Fde A
authors.lastname: Vilas-Boas
authors.affiliation: Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Aristóbolo Mendes
authors.initials: AM
authors.lastname: da Silva
authors.affiliation: Department of Clinical and Toxicological Analysis, Pharmacy Faculty, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Lirlândia Pires
authors.initials: LP
authors.lastname: de Sousa
authors.affiliation: Department of Clinical and Toxicological Analysis, Pharmacy Faculty, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Kátia Maciel
authors.initials: KM
authors.lastname: Lima
authors.affiliation: Department of Clinical and Toxicological Analysis, Pharmacy Faculty, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Juliana Priscila
authors.initials: JP
authors.lastname: Vago
authors.affiliation: Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Lucas Felipe Fernandes
authors.initials: LF
authors.lastname: Bittencourt
authors.affiliation: Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Arthur Estanislau
authors.initials: AE
authors.lastname: Dantas
authors.affiliation: Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Dawidson Assis
authors.initials: DA
authors.lastname: Gomes
authors.affiliation: Department of Health Sciences, Federal University of Juiz de Fora-Advanced Campus, Governador Valadares, Minas Gerais, 35010-177, Brazil.
authors.forename: Márcia Carvalho
authors.initials: MC
authors.lastname: Vilela
authors.affiliation: Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Mauro Martins
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil. luciolasbarcelos@gmail.com.|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. luciolasbarcelos@gmail.com.
authors.forename: Lucíola Silva
authors.initials: LS
authors.lastname: Barcelos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2
keywords: Chemotherapy; Glioma; Integrated stress response; Stress granules; eIF2α