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1.
Cancer Res ; 79(10): 2536-2548, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30940658

RESUMO

Alkylating chemotherapy is a central component of the management of glioblastoma (GBM). Among the factors that regulate the response to alkylation damage, NF-κB acts to both promote and block cytotoxicity. In this study, we used genome-wide expression analysis in U87 GBM to identify NF-κB-dependent factors altered in response to temozolomide and found the long noncoding RNA (lncRNA) MALAT1 as one of the most significantly upregulated. In addition, we demonstrated that MALAT1 expression was coregulated by p50 (p105) and p53 via novel κB- and p53-binding sites in the proximal MALAT1 coding region. Temozolomide treatment inhibited p50 recruitment to its cognate element as a function of Ser329 phosphorylation while concomitantly increasing p53 recruitment. Moreover, luciferase reporter studies demonstrated that both κB and p53 cis-elements were required for efficient transactivation in response to temozolomide. Depletion of MALAT1 sensitized patient-derived GBM cells to temozolomide cytotoxicity, and in vivo delivery of nanoparticle-encapsulated anti-MALAT1 siRNA increased the efficacy of temozolomide in mice bearing intracranial GBM xenografts. Despite these observations, in situ hybridization of GBM specimens and analysis of publicly available datasets revealed that MALAT1 expression within GBM tissue was not prognostic of overall survival. Together, these findings support MALAT1 as a target for chemosensitization of GBM and identify p50 and p52 as primary regulators of this ncRNA. SIGNIFICANCE: These findings identify NF-κB and p53 as regulators of the lncRNA MALAT1 and suggest MALAT1 as a potential target for the chemosensitization of GBM.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/metabolismo , Glioblastoma/tratamento farmacológico , NF-kappa B/metabolismo , RNA Longo não Codificante/biossíntese , Temozolomida/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Dano ao DNA/genética , Técnicas de Silenciamento de Genes , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Prognóstico , RNA Longo não Codificante/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Res ; 75(10): 2039-48, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25808868

RESUMO

Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53(+/+) glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Dacarbazina/análogos & derivados , Subunidade p50 de NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/metabolismo , Receptores Chamariz do Fator de Necrose Tumoral/genética , Animais , Proteína 3 do Linfoma de Células B , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/metabolismo , Humanos , Masculino , Camundongos Nus , Regiões Promotoras Genéticas , Ligação Proteica , Membro 10c de Receptores do Fator de Necrose Tumoral , Temozolomida , Ativação Transcricional , Receptores Chamariz do Fator de Necrose Tumoral/química , Receptores Chamariz do Fator de Necrose Tumoral/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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