53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM-CHK2-P53 pathway.
J Cancer Res Clin Oncol
; 143(3): 419-431, 2017 Mar.
Article
em En
| MEDLINE
| ID: mdl-27838786
ABSTRACT
PURPOSE:
Loss of P53 binding protein 1 (53BP1) is considered a poor prognostic factor for colorectal cancer. However, its effect on chemosensitivity of colorectal cancer to 5-fluorouracil (5-FU) remains elusive. This study aimed to examine the association of 53BP1 expression with chemosensitivity of colorectal cancer cells to 5-FU.METHODS:
Immunohistochemistry was performed on 30 metastatic colorectal cancer samples to assess the associations of 53BP1 levels with clinical therapeutic effects. In vitro, IC50 values for 5-FU and 53BP1 levels were determined by MTT assay and Western blot in 5 colorectal cancer cell lines. Then, 53BP1 was silenced in HCT116 and HT29 cells, and cell proliferation, apoptosis and cell cycle distribution were evaluated. Relative protein levels of ATM-CHK2-P53 pathway effectors and Bcl-2 family members were measured by Western blot. Finally, the effects of 53BP1 knockdown on tumor growth and 5-FU chemoresistance were investigated in vivo.RESULTS:
53BP1 expression was closely related to time to progression (TTP) after first-line chemotherapy. Namely, 53BP1 downregulation resulted in reduced TTP. In addition, 53BP1 silencing increased proliferation, inhibited apoptosis and induced S phase arrest in HCT116 and HT29 cells after 5-FU treatment. Moreover, 53BP1 knockdown also reduced the protein levels of ATM-CHK2-P53 apoptotic pathway effectors, caspase9 and caspase3, while increasing Bcl-2 expression. In vivo, 53BP1 silencing accelerated tumor proliferation in nude mice and enhanced resistance to 5-FU.CONCLUSIONS:
These findings confirmed that 53BP1 loss might be a negative factor for chemotherapy efficacy, promoting cell proliferation and inhibiting apoptosis by suppressing ATM-CHK2-P53 signaling, and finally inducing 5-FU resistance.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Proteína Supressora de Tumor p53
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Proteínas Mutadas de Ataxia Telangiectasia
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Quinase do Ponto de Checagem 2
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Proteína 1 de Ligação à Proteína Supressora de Tumor p53
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article