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Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy
The development of resistance to chemotherapeutic agents, such as Doxorubicin (DOX) and cytarabine (AraC), is one of the greatest challenges to the successful treatment of Acute Myeloid Leukemia (AML). Such acquisition is often underlined by a metabolic reprogramming that can provide a therapeutic o...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Research Network of Computational and Structural Biotechnology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326745/ https://www.ncbi.nlm.nih.gov/pubmed/34377370 http://dx.doi.org/10.1016/j.csbj.2021.06.049 |
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author | Karakitsou, Effrosyni Foguet, Carles Contreras Mostazo, Miriam G. Kurrle, Nina Schnütgen, Frank Michaelis, Martin Cinatl, Jindrich Marin, Silvia Cascante, Marta |
author_facet | Karakitsou, Effrosyni Foguet, Carles Contreras Mostazo, Miriam G. Kurrle, Nina Schnütgen, Frank Michaelis, Martin Cinatl, Jindrich Marin, Silvia Cascante, Marta |
author_sort | Karakitsou, Effrosyni |
collection | PubMed |
description | The development of resistance to chemotherapeutic agents, such as Doxorubicin (DOX) and cytarabine (AraC), is one of the greatest challenges to the successful treatment of Acute Myeloid Leukemia (AML). Such acquisition is often underlined by a metabolic reprogramming that can provide a therapeutic opportunity, as it can lead to the emergence of vulnerabilities and dependencies to be exploited as targets against the resistant cells. In this regard, genome-scale metabolic models (GSMMs) have emerged as powerful tools to integrate multiple layers of data to build cancer-specific models and identify putative metabolic vulnerabilities. Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate. Moreover, we discovered and validated that the resistant cell lines could be selectively targeted by inhibiting squalene synthase, providing a new and promising strategy to directly inhibit cholesterol synthesis in AML drug resistant cells. |
format | Online Article Text |
id | pubmed-8326745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Research Network of Computational and Structural Biotechnology |
record_format | MEDLINE/PubMed |
spelling | pubmed-83267452021-08-09 Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy Karakitsou, Effrosyni Foguet, Carles Contreras Mostazo, Miriam G. Kurrle, Nina Schnütgen, Frank Michaelis, Martin Cinatl, Jindrich Marin, Silvia Cascante, Marta Comput Struct Biotechnol J Research Article The development of resistance to chemotherapeutic agents, such as Doxorubicin (DOX) and cytarabine (AraC), is one of the greatest challenges to the successful treatment of Acute Myeloid Leukemia (AML). Such acquisition is often underlined by a metabolic reprogramming that can provide a therapeutic opportunity, as it can lead to the emergence of vulnerabilities and dependencies to be exploited as targets against the resistant cells. In this regard, genome-scale metabolic models (GSMMs) have emerged as powerful tools to integrate multiple layers of data to build cancer-specific models and identify putative metabolic vulnerabilities. Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate. Moreover, we discovered and validated that the resistant cell lines could be selectively targeted by inhibiting squalene synthase, providing a new and promising strategy to directly inhibit cholesterol synthesis in AML drug resistant cells. Research Network of Computational and Structural Biotechnology 2021-07-08 /pmc/articles/PMC8326745/ /pubmed/34377370 http://dx.doi.org/10.1016/j.csbj.2021.06.049 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Karakitsou, Effrosyni Foguet, Carles Contreras Mostazo, Miriam G. Kurrle, Nina Schnütgen, Frank Michaelis, Martin Cinatl, Jindrich Marin, Silvia Cascante, Marta Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy |
title | Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy |
title_full | Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy |
title_fullStr | Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy |
title_full_unstemmed | Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy |
title_short | Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy |
title_sort | genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against aml cells resistant to chemotherapy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326745/ https://www.ncbi.nlm.nih.gov/pubmed/34377370 http://dx.doi.org/10.1016/j.csbj.2021.06.049 |
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