BCL3 expression promotes resistance to alkylating chemotherapy in gliomas.
Sci Transl Med
; 10(448)2018 07 04.
Article
em En
| MEDLINE
| ID: mdl-29973405
ABSTRACT
The response of patients with gliomas to alkylating chemotherapy is heterogeneous. However, there are currently no universally accepted predictors of patient response to these agents. We identify the nuclear factor κB (NF-κB) co-regulator B cell CLL/lymphoma 3 (BCL-3) as an independent predictor of response to temozolomide (TMZ) treatment. In glioma patients with tumors that have a methylated O6-methylguanine DNA methyltransferase (MGMT) promoter, high BCL-3 expression was associated with a poor response to TMZ. Mechanistically, BCL-3 promoted a more malignant phenotype by inducing an epithelial-to-mesenchymal transition in glioblastomas through promoter-specific NF-κB dimer exchange. Carbonic anhydrase II (CAII) was identified as a downstream factor promoting BCL-3-mediated resistance to chemotherapy. Experiments in glioma xenograft mouse models demonstrated that the CAII inhibitor acetazolamide enhanced survival of TMZ-treated animals. Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Neoplasias Encefálicas
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Regulação Neoplásica da Expressão Gênica
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Proteínas Proto-Oncogênicas
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Resistencia a Medicamentos Antineoplásicos
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Antineoplásicos Alquilantes
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Glioma
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article