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ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner
Patients with advanced biliary tract cancer (BTC) inevitably experience progression after first-line, gemcitabine-based chemotherapy, due to chemo-resistance. The genetic alterations of DNA damage repair (DDR) genes are usually determined in BTC tumors. In this study, we found that the POLQ mRNA lev...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697425/ https://www.ncbi.nlm.nih.gov/pubmed/33182492 http://dx.doi.org/10.3390/biom10111529 |
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author | Pan, Yi-Ru Wu, Chiao-En Yeh, Chun-Nan |
author_facet | Pan, Yi-Ru Wu, Chiao-En Yeh, Chun-Nan |
author_sort | Pan, Yi-Ru |
collection | PubMed |
description | Patients with advanced biliary tract cancer (BTC) inevitably experience progression after first-line, gemcitabine-based chemotherapy, due to chemo-resistance. The genetic alterations of DNA damage repair (DDR) genes are usually determined in BTC tumors. In this study, we found that the POLQ mRNA levels are downregulated and the ataxia-telangiectasia mutated (ATM) inhibitor AZD0156 was more sensitive in gemcitabine-resistant BTC sublines than in the parental cell lines. The knockdown of DNA polymerase θ does not affect cell proliferation, but its combination with the ATM inhibitor facilitated cell death in gemcitabine-resistant and gemcitabine-intensive BTC cells. Moreover, in the DNA damage caused by photon, hydrogen peroxide, or chemotherapy drugs, synthetic lethal interactions were found in combination with ATM inhibition by AZD0156 and DNA polymerase θ depletion, resulting in increased DNA damage accumulation and micronucleus formation, as well as reduced cell survival and colony formation. Collectively, our results reveal that ATM acts as a potential target in gemcitabine-resistant and DNA polymerase θ-deficient BTC. |
format | Online Article Text |
id | pubmed-7697425 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76974252020-11-29 ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner Pan, Yi-Ru Wu, Chiao-En Yeh, Chun-Nan Biomolecules Article Patients with advanced biliary tract cancer (BTC) inevitably experience progression after first-line, gemcitabine-based chemotherapy, due to chemo-resistance. The genetic alterations of DNA damage repair (DDR) genes are usually determined in BTC tumors. In this study, we found that the POLQ mRNA levels are downregulated and the ataxia-telangiectasia mutated (ATM) inhibitor AZD0156 was more sensitive in gemcitabine-resistant BTC sublines than in the parental cell lines. The knockdown of DNA polymerase θ does not affect cell proliferation, but its combination with the ATM inhibitor facilitated cell death in gemcitabine-resistant and gemcitabine-intensive BTC cells. Moreover, in the DNA damage caused by photon, hydrogen peroxide, or chemotherapy drugs, synthetic lethal interactions were found in combination with ATM inhibition by AZD0156 and DNA polymerase θ depletion, resulting in increased DNA damage accumulation and micronucleus formation, as well as reduced cell survival and colony formation. Collectively, our results reveal that ATM acts as a potential target in gemcitabine-resistant and DNA polymerase θ-deficient BTC. MDPI 2020-11-09 /pmc/articles/PMC7697425/ /pubmed/33182492 http://dx.doi.org/10.3390/biom10111529 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Pan, Yi-Ru Wu, Chiao-En Yeh, Chun-Nan ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner |
title | ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner |
title_full | ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner |
title_fullStr | ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner |
title_full_unstemmed | ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner |
title_short | ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner |
title_sort | atm inhibitor suppresses gemcitabine-resistant btc growth in a polymerase θ deficiency-dependent manner |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697425/ https://www.ncbi.nlm.nih.gov/pubmed/33182492 http://dx.doi.org/10.3390/biom10111529 |
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