Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway.
Oncotarget
; 8(27): 43733-43751, 2017 Jul 04.
Article
em En
| MEDLINE
| ID: mdl-28415827
ABSTRACT
Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Camptotecina
/
DNA Topoisomerases Tipo I
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Resistencia a Medicamentos Antineoplásicos
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Ubiquitina
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Complexo de Endopeptidases do Proteassoma
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Inibidores da Topoisomerase I
Limite:
Humans
Idioma:
En
Revista:
Oncotarget
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos