IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer.
Mol Cell
; 75(4): 669-682.e5, 2019 08 22.
Article
em En
| MEDLINE
| ID: mdl-31302002
ABSTRACT
Phosphorylated IKKα(p45) is a nuclear active form of the IKKα kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-κB signaling. Insights into the sources of IKKα(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKα(p45) is rapidly activated by DNA damage independent of ATM-ATR, but dependent on BRAF-TAK1-p38-MAPK, and is required for robust ATM activation and efficient DNA repair. Abolishing BRAF or IKKα activity attenuates ATM, Chk1, MDC1, Kap1, and 53BP1 phosphorylation, compromises 53BP1 and RIF1 co-recruitment to sites of DNA lesions, and inhibits 53BP1-dependent fusion of dysfunctional telomeres. Furthermore, IKKα or BRAF inhibition synergistically enhances the therapeutic potential of 5-FU and irinotecan to eradicate chemotherapy-resistant metastatic human tumors in vivo. Our results implicate BRAF and IKKα kinases in the DDR and reveal a combination strategy for cancer treatment.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Resistencia a Medicamentos Antineoplásicos
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Sistema de Sinalização das MAP Quinases
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Quinase I-kappa B
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Fluoruracila
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Irinotecano
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Proteínas de Neoplasias
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Neoplasias
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article