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Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers

Rationale: The human ligases (LIG1, LIG3 and LIG4) are essential for the maintenance of genomic integrity by catalysing the formation of phosphodiester bonds between adjacent 5′-phosphoryl and 3′-hydroxyl termini at single and double strand breaks in duplex DNA molecules generated either directly by...

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Autores principales: Ali, Reem, Alabdullah, Muslim, Algethami, Mashael, Alblihy, Adel, Miligy, Islam, Shoqafi, Ahmed, Mesquita, Katia A., Abdel-Fatah, Tarek, Chan, Stephen YT, Chiang, Pei Wen, Mongan, Nigel P, Rakha, Emad A, Tomkinson, Alan E, Madhusudan, Srinivasan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344016/
https://www.ncbi.nlm.nih.gov/pubmed/34373746
http://dx.doi.org/10.7150/thno.51456
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author Ali, Reem
Alabdullah, Muslim
Algethami, Mashael
Alblihy, Adel
Miligy, Islam
Shoqafi, Ahmed
Mesquita, Katia A.
Abdel-Fatah, Tarek
Chan, Stephen YT
Chiang, Pei Wen
Mongan, Nigel P
Rakha, Emad A
Tomkinson, Alan E
Madhusudan, Srinivasan
author_facet Ali, Reem
Alabdullah, Muslim
Algethami, Mashael
Alblihy, Adel
Miligy, Islam
Shoqafi, Ahmed
Mesquita, Katia A.
Abdel-Fatah, Tarek
Chan, Stephen YT
Chiang, Pei Wen
Mongan, Nigel P
Rakha, Emad A
Tomkinson, Alan E
Madhusudan, Srinivasan
author_sort Ali, Reem
collection PubMed
description Rationale: The human ligases (LIG1, LIG3 and LIG4) are essential for the maintenance of genomic integrity by catalysing the formation of phosphodiester bonds between adjacent 5′-phosphoryl and 3′-hydroxyl termini at single and double strand breaks in duplex DNA molecules generated either directly by DNA damage or during replication, recombination, and DNA repair. Whether LIG1, LIG3 and LIG4 can influence ovarian cancer pathogenesis and therapeutics is largely unknown. Methods: We investigated LIG1, LIG3 and LIG4 expression in clinical cohorts of epithelial ovarian cancers [protein level (n=525) and transcriptional level (n=1075)] and correlated to clinicopathological features and survival outcomes. Pre-clinically, platinum sensitivity was investigated in LIG1 depleted ovarian cancer cells. A small molecule inhibitor of LIG1 (L82) was tested for synthetic lethality application in XRCC1, BRCA2 or ATM deficient cancer cells. Results: LIG1 and LIG3 overexpression linked with aggressive phenotypes, platinum resistance and poor progression free survival (PFS). In contrast, LIG4 deficiency was associated with platinum resistance and worse PFS. In a multivariate analysis, LIG1 was independently associated with adverse outcome. In ovarian cancer cell lines, LIG1 depletion increased platinum cytotoxicity. L82 monotherapy was synthetically lethal in XRCC1 deficient ovarian cancer cells and 3D-spheroids. Increased cytotoxicity was linked with accumulation of DNA double strand breaks (DSBs), S-phase cell cycle arrest and increased apoptotic cells. L82 was also selectively toxic in BRCA2 deficient or ATM deficient cancer cells and 3D-spheroids. Conclusions: We provide evidence that LIG1 is an attractive target for personalization of ovarian cancer therapy.
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spelling pubmed-83440162021-08-08 Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers Ali, Reem Alabdullah, Muslim Algethami, Mashael Alblihy, Adel Miligy, Islam Shoqafi, Ahmed Mesquita, Katia A. Abdel-Fatah, Tarek Chan, Stephen YT Chiang, Pei Wen Mongan, Nigel P Rakha, Emad A Tomkinson, Alan E Madhusudan, Srinivasan Theranostics Research Paper Rationale: The human ligases (LIG1, LIG3 and LIG4) are essential for the maintenance of genomic integrity by catalysing the formation of phosphodiester bonds between adjacent 5′-phosphoryl and 3′-hydroxyl termini at single and double strand breaks in duplex DNA molecules generated either directly by DNA damage or during replication, recombination, and DNA repair. Whether LIG1, LIG3 and LIG4 can influence ovarian cancer pathogenesis and therapeutics is largely unknown. Methods: We investigated LIG1, LIG3 and LIG4 expression in clinical cohorts of epithelial ovarian cancers [protein level (n=525) and transcriptional level (n=1075)] and correlated to clinicopathological features and survival outcomes. Pre-clinically, platinum sensitivity was investigated in LIG1 depleted ovarian cancer cells. A small molecule inhibitor of LIG1 (L82) was tested for synthetic lethality application in XRCC1, BRCA2 or ATM deficient cancer cells. Results: LIG1 and LIG3 overexpression linked with aggressive phenotypes, platinum resistance and poor progression free survival (PFS). In contrast, LIG4 deficiency was associated with platinum resistance and worse PFS. In a multivariate analysis, LIG1 was independently associated with adverse outcome. In ovarian cancer cell lines, LIG1 depletion increased platinum cytotoxicity. L82 monotherapy was synthetically lethal in XRCC1 deficient ovarian cancer cells and 3D-spheroids. Increased cytotoxicity was linked with accumulation of DNA double strand breaks (DSBs), S-phase cell cycle arrest and increased apoptotic cells. L82 was also selectively toxic in BRCA2 deficient or ATM deficient cancer cells and 3D-spheroids. Conclusions: We provide evidence that LIG1 is an attractive target for personalization of ovarian cancer therapy. Ivyspring International Publisher 2021-07-25 /pmc/articles/PMC8344016/ /pubmed/34373746 http://dx.doi.org/10.7150/thno.51456 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Ali, Reem
Alabdullah, Muslim
Algethami, Mashael
Alblihy, Adel
Miligy, Islam
Shoqafi, Ahmed
Mesquita, Katia A.
Abdel-Fatah, Tarek
Chan, Stephen YT
Chiang, Pei Wen
Mongan, Nigel P
Rakha, Emad A
Tomkinson, Alan E
Madhusudan, Srinivasan
Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers
title Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers
title_full Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers
title_fullStr Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers
title_full_unstemmed Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers
title_short Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers
title_sort ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in xrcc1 deficient epithelial ovarian cancers
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344016/
https://www.ncbi.nlm.nih.gov/pubmed/34373746
http://dx.doi.org/10.7150/thno.51456
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