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Journal of Cancer Research and Clinical Oncology

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01-03-2017 | Original Article – Cancer Research

53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM–CHK2–P53 pathway

Authors: Jing Yao, Ai Huang, Xiumei Zheng, Tao Liu, Zhenyu Lin, Sheng Zhang, Qin Yang, Tao Zhang, Hong Ma

Published in: Journal of Cancer Research and Clinical Oncology | Issue 3/2017

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.

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Title: 53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM–CHK2–P53 pathway
Authors: Jing Yao
Ai Huang
Xiumei Zheng
Tao Liu
Zhenyu Lin
Sheng Zhang
Qin Yang
Tao Zhang
Hong Ma
Publication date: 01-03-2017
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 3/2017
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-016-2302-5

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53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM–CHK2–P53 pathway

Abstract

Purpose

Methods

Results

Conclusions

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Abstract

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