Targeting the DNA replication checkpoint by pharmacologic inhibition of Chk1 kinase: a strategy to sensitize APC mutant colon cancer cells to 5-fluorouracil chemotherapy.
Oncotarget
; 5(20): 9889-900, 2014 Oct 30.
Article
en En
| MEDLINE
| ID: mdl-25301724
5-fluorouracil (5-FU) is the first line component used in colorectal cancer (CRC) therapy however even in combination with other chemotherapeutic drugs recurrence is common. Mutations of the adenomatous polyposis coli (APC) gene are considered as the initiating step of transformation in familial and sporadic CRCs. We have previously shown that APC regulates the cellular response to DNA replication stress and recently hypothesized that APC mutations might therefore influence 5-FU resistance. To test this, we compared CRC cell lines and show that those expressing truncated APC exhibit a limited response to 5-FU and arrest in G1/S-phase without undergoing lethal damage, unlike cells expressing wild-type APC. In SW480 APC-mutant CRC cells, 5-FU-dependent apoptosis was restored after transient expression of full length APC, indicating a direct link between APC and drug response. Furthermore, we could increase sensitivity of APC truncated cells to 5-FU by inactivating the Chk1 kinase using drug treatment or siRNA-mediated knockdown. Our findings identify mutant APC as a potential tumor biomarker of resistance to 5-FU, and importantly we show that APC-mutant CRC cells can be made more sensitive to 5-FU by use of Chk1 inhibitors.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas
/
ADN de Neoplasias
/
Neoplasias Colorrectales
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Inhibidores de Proteínas Quinasas
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Replicación del ADN
/
Fluorouracilo
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Oncotarget
Año:
2014
Tipo del documento:
Article
País de afiliación:
Australia
Pais de publicación:
Estados Unidos