BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells

Acquired drug tolerance has been a major challenge in cancer therapy. Recent evidence has revealed the existence of slow-cycling persister cells that survive drug treatments and give rise to multi-drug-tolerant mutants in cancer. Cells in this dynamic persister state can escape drug treatment by und...

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Autores principales:	Prashant Karki, Shayne Sensenbach, Vahideh Angardi, Mehmet A. Orman
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cancer persisters BRAF melanoma metabolomics phenotype microarrays drug-tolerance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/db0b950860524ae599b0540883669795
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spelling	oai:doaj.org-article:db0b950860524ae599b05408836697952021-11-25T18:20:51ZBRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells10.3390/metabo111107772218-1989https://doaj.org/article/db0b950860524ae599b05408836697952021-11-01T00:00:00Zhttps://www.mdpi.com/2218-1989/11/11/777https://doaj.org/toc/2218-1989Acquired drug tolerance has been a major challenge in cancer therapy. Recent evidence has revealed the existence of slow-cycling persister cells that survive drug treatments and give rise to multi-drug-tolerant mutants in cancer. Cells in this dynamic persister state can escape drug treatment by undergoing various epigenetic changes, which may result in a transient metabolic rewiring. In this study, with the use of untargeted metabolomics and phenotype microarrays, we characterize the metabolic profiles of melanoma persister cells mediated by treatment with vemurafenib, a BRAF inhibitor. Our findings demonstrate that metabolites associated with phospholipid synthesis, pyrimidine, and one-carbon metabolism and branched-chain amino acid metabolism are significantly altered in vemurafenib persister cells when compared to the bulk cancer population. Our data also show that vemurafenib persisters have higher lactic acid consumption rates than control cells, further validating the existence of a unique metabolic reprogramming in these drug-tolerant cells. Determining the metabolic mechanisms underlying persister cell survival and maintenance will facilitate the development of novel treatment strategies that target persisters and enhance cancer therapy.Prashant KarkiShayne SensenbachVahideh AngardiMehmet A. OrmanMDPI AGarticlecancer persistersBRAFmelanomametabolomicsphenotype microarraysdrug-toleranceMicrobiologyQR1-502ENMetabolites, Vol 11, Iss 777, p 777 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer persisters BRAF melanoma metabolomics phenotype microarrays drug-tolerance Microbiology QR1-502
spellingShingle	cancer persisters BRAF melanoma metabolomics phenotype microarrays drug-tolerance Microbiology QR1-502 Prashant Karki Shayne Sensenbach Vahideh Angardi Mehmet A. Orman BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells
description	Acquired drug tolerance has been a major challenge in cancer therapy. Recent evidence has revealed the existence of slow-cycling persister cells that survive drug treatments and give rise to multi-drug-tolerant mutants in cancer. Cells in this dynamic persister state can escape drug treatment by undergoing various epigenetic changes, which may result in a transient metabolic rewiring. In this study, with the use of untargeted metabolomics and phenotype microarrays, we characterize the metabolic profiles of melanoma persister cells mediated by treatment with vemurafenib, a BRAF inhibitor. Our findings demonstrate that metabolites associated with phospholipid synthesis, pyrimidine, and one-carbon metabolism and branched-chain amino acid metabolism are significantly altered in vemurafenib persister cells when compared to the bulk cancer population. Our data also show that vemurafenib persisters have higher lactic acid consumption rates than control cells, further validating the existence of a unique metabolic reprogramming in these drug-tolerant cells. Determining the metabolic mechanisms underlying persister cell survival and maintenance will facilitate the development of novel treatment strategies that target persisters and enhance cancer therapy.
format	article
author	Prashant Karki Shayne Sensenbach Vahideh Angardi Mehmet A. Orman
author_facet	Prashant Karki Shayne Sensenbach Vahideh Angardi Mehmet A. Orman
author_sort	Prashant Karki
title	BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells
title_short	BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells
title_full	BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells
title_fullStr	BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells
title_full_unstemmed	BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells
title_sort	braf-inhibitor-induced metabolic alterations in a375 melanoma cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/db0b950860524ae599b0540883669795
work_keys_str_mv	AT prashantkarki brafinhibitorinducedmetabolicalterationsina375melanomacells AT shaynesensenbach brafinhibitorinducedmetabolicalterationsina375melanomacells AT vahidehangardi brafinhibitorinducedmetabolicalterationsina375melanomacells AT mehmetaorman brafinhibitorinducedmetabolicalterationsina375melanomacells
_version_	1718411350305144832

BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells

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