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Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival

Cisplatin exert its anticancer effect by creating intrastrand and interstrand DNA cross-links which block DNA replication and is a major drug used to treat lung cancer. However, the main obstacle of the efficacy of treatment is drug resistance. Here, we show that expression of translesion synthesis...

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Autores principales: Dai, Chun-Hua, Chen, Ping, Li, Jian, Lan, Tin, Chen, Yong-Chang, Qian, Hai, Chen, Kang, Li, Mei-Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323145/
https://www.ncbi.nlm.nih.gov/pubmed/27533083
http://dx.doi.org/10.18632/oncotarget.11214
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author Dai, Chun-Hua
Chen, Ping
Li, Jian
Lan, Tin
Chen, Yong-Chang
Qian, Hai
Chen, Kang
Li, Mei-Yu
author_facet Dai, Chun-Hua
Chen, Ping
Li, Jian
Lan, Tin
Chen, Yong-Chang
Qian, Hai
Chen, Kang
Li, Mei-Yu
author_sort Dai, Chun-Hua
collection PubMed
description Cisplatin exert its anticancer effect by creating intrastrand and interstrand DNA cross-links which block DNA replication and is a major drug used to treat lung cancer. However, the main obstacle of the efficacy of treatment is drug resistance. Here, we show that expression of translesion synthesis (TLS) polymerase Q (POLQ) was significantly elevated by exposure of lung cancer cells A549/DR (a cisplatin-resistant A549 cell line) to cisplatin. POLQ expression correlated inversely with homologous recombination (HR) activity. Co-depletion of BRCA2 and POLQ by siRNA markedly increased sensitivity of A549/DR cells to cisplatin, which was accompanied with impairment of double strand breaks (DSBs) repair reflected by prominent cell cycle checkpoint response, increased chromosomal aberrations and persistent colocalization of p-ATM and 53BP1 foci induced by cisplatin. Thus, co-knockdown of POLQ and HR can efficiently synergize with cisplatin to inhibit A549/DR cell survival by inhibiting DNA DSBs repair. Similar results were observed in A549/DR cells co-depleted of BRCA2 and POLQ following BMN673 (a PARP inhibitor) treatment. Importantly, the sensitization effects to cisplatin and BMN673 in A549/DR cells by co-depleting BRCA2 and POLQ was stronger than those by co-depleting BRCA2 and other TLS factors including POLH, REV3, or REV1. Our results indicate that there is a synthetic lethal relationship between pol θ-mediated DNA repair and HR pathways. Pol θ may be considered as a novel target for lung cancer therapy.
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spelling pubmed-53231452017-03-23 Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival Dai, Chun-Hua Chen, Ping Li, Jian Lan, Tin Chen, Yong-Chang Qian, Hai Chen, Kang Li, Mei-Yu Oncotarget Research Paper Cisplatin exert its anticancer effect by creating intrastrand and interstrand DNA cross-links which block DNA replication and is a major drug used to treat lung cancer. However, the main obstacle of the efficacy of treatment is drug resistance. Here, we show that expression of translesion synthesis (TLS) polymerase Q (POLQ) was significantly elevated by exposure of lung cancer cells A549/DR (a cisplatin-resistant A549 cell line) to cisplatin. POLQ expression correlated inversely with homologous recombination (HR) activity. Co-depletion of BRCA2 and POLQ by siRNA markedly increased sensitivity of A549/DR cells to cisplatin, which was accompanied with impairment of double strand breaks (DSBs) repair reflected by prominent cell cycle checkpoint response, increased chromosomal aberrations and persistent colocalization of p-ATM and 53BP1 foci induced by cisplatin. Thus, co-knockdown of POLQ and HR can efficiently synergize with cisplatin to inhibit A549/DR cell survival by inhibiting DNA DSBs repair. Similar results were observed in A549/DR cells co-depleted of BRCA2 and POLQ following BMN673 (a PARP inhibitor) treatment. Importantly, the sensitization effects to cisplatin and BMN673 in A549/DR cells by co-depleting BRCA2 and POLQ was stronger than those by co-depleting BRCA2 and other TLS factors including POLH, REV3, or REV1. Our results indicate that there is a synthetic lethal relationship between pol θ-mediated DNA repair and HR pathways. Pol θ may be considered as a novel target for lung cancer therapy. Impact Journals LLC 2016-08-11 /pmc/articles/PMC5323145/ /pubmed/27533083 http://dx.doi.org/10.18632/oncotarget.11214 Text en Copyright: © 2016 Dai et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Dai, Chun-Hua
Chen, Ping
Li, Jian
Lan, Tin
Chen, Yong-Chang
Qian, Hai
Chen, Kang
Li, Mei-Yu
Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival
title Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival
title_full Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival
title_fullStr Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival
title_full_unstemmed Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival
title_short Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival
title_sort co-inhibition of pol θ and hr genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323145/
https://www.ncbi.nlm.nih.gov/pubmed/27533083
http://dx.doi.org/10.18632/oncotarget.11214
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