Targeting the DNA replication checkpoint by pharmacologic inhibition of Chk1 kinase: a strategy to sensitize APC mutant colon cancer cells to 5-fluorouracil chemotherapy

Estefania Martino-Echarri, Beric R. Henderson, Mariana G. Brocardo

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

LanguageEnglish
Pages9889-9900
Number of pages12
JournalOncotarget
Volume5
Issue number20
Publication statusPublished - 2014
Externally publishedYes

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Adenomatous Polyposis Coli
DNA Replication
Fluorouracil
Colonic Neoplasms
Drug Therapy
Colorectal Neoplasms
Checkpoint Kinase 1
Pharmaceutical Preparations
APC Genes
Mutation
G1 Phase
Tumor Biomarkers
S Phase
Small Interfering RNA
Apoptosis
Recurrence
Cell Line

Bibliographical note

Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this

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title = "Targeting the DNA replication checkpoint by pharmacologic inhibition of Chk1 kinase: a strategy to sensitize APC mutant colon cancer cells to 5-fluorouracil chemotherapy",
abstract = "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.",
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Targeting the DNA replication checkpoint by pharmacologic inhibition of Chk1 kinase : a strategy to sensitize APC mutant colon cancer cells to 5-fluorouracil chemotherapy. / Martino-Echarri, Estefania; Henderson, Beric R.; Brocardo, Mariana G.

In: Oncotarget, Vol. 5, No. 20, 2014, p. 9889-9900.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Targeting the DNA replication checkpoint by pharmacologic inhibition of Chk1 kinase

T2 - Oncotarget

AU - Martino-Echarri, Estefania

AU - Henderson, Beric R.

AU - Brocardo, Mariana G.

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PY - 2014

Y1 - 2014

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