ORCID Profile
0000-0001-7473-7433
Current Organisation
Universidade Federal de Minas Gerais
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Publisher: Elsevier BV
Date: 04-2007
Publisher: Informa UK Limited
Date: 2003
Publisher: Springer Science and Business Media LLC
Date: 05-01-2016
DOI: 10.1007/S11060-015-2043-3
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.
Publisher: Elsevier BV
Date: 05-2003
Publisher: Elsevier BV
Date: 09-2004
Publisher: Mary Ann Liebert Inc
Date: 10-2012
Abstract: Double-stranded RNA dependent protein kinase (PKR) is a host defense enzyme whose expression is up-regulated in response to interferons (IFNs) and during viral infections. Increased levels of PKR can result in its activation, which, in turn, inhibits global cellular protein synthesis. Despite growing evidence suggesting the involvement of PKR in bacterial infections, little is known about its expression, regulation and cellular role in nonviral infections. The aim of this work was to determine the expression and regulation of PKR in response to stimulation of human THP-1 monocytes with bacterial agonists of TLR2/4. Treatment of cells with Pam3CSK4 or lipopolyssacharide (LPS) resulted in an increase in PKR mRNA and protein levels. Robust PKR expression at later times correlated with a decrease in global protein synthesis. PKR was also required to regulate the inhibition of protein synthesis triggered by LPS in mouse splenocytes. Surprisingly, no increase of IFN-β or IFN-α mRNA levels was detected after treatment of THP-1 cells with toll-like receptor (TLR) agonists. In accordance with this, the supernatants from LPS or Pam3CSK4-treated cells lacked the ability to activate the PKR and ISG56 promoters in gene reporter assays carried out in HEK293T cells. The expression of PKR induced by TLRs agonists was dramatically impaired when cells were treated in the presence of tosyl-phenylalanyl chloromethylketone or Mithramycin, suggesting that NF-κB and Sp1 transcription factors, but not those activated by IFNs, regulate the expression of PKR in human monocytes.
No related grants have been discovered for Aristóbolo Silva.