Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.

The chemotherapeutic compound, cisplatin causes various kinds of DNA lesions but also triggers other pertubations, such as ER and oxidative stress. We and others have shown that treatment of pluripotent stem cells with cisplatin causes a plethora of transcriptional and post-translational alterations...

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Autores principales:	Louise von Stechow, Ainhoa Ruiz-Aracama, Bob van de Water, Ad Peijnenburg, Erik Danen, Arjen Lommen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/790b6b9894b74c379669e034e7c6175f
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spelling	oai:doaj.org-article:790b6b9894b74c379669e034e7c6175f2021-11-18T08:50:48ZIdentification of cisplatin-regulated metabolic pathways in pluripotent stem cells.1932-620310.1371/journal.pone.0076476https://doaj.org/article/790b6b9894b74c379669e034e7c6175f2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24146875/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The chemotherapeutic compound, cisplatin causes various kinds of DNA lesions but also triggers other pertubations, such as ER and oxidative stress. We and others have shown that treatment of pluripotent stem cells with cisplatin causes a plethora of transcriptional and post-translational alterations that, to a major extent, point to DNA damage response (DDR) signaling. The orchestrated DDR signaling network is important to arrest the cell cycle and repair the lesions or, in case of damage beyond repair, eliminate affected cells. Failure to properly balance the various aspects of the DDR in stem cells contributes to ageing and cancer. Here, we performed metabolic profiling by mass spectrometry of embryonic stem (ES) cells treated for different time periods with cisplatin. We then integrated metabolomics with transcriptomics analyses and connected cisplatin-regulated metabolites with regulated metabolic enzymes to identify enriched metabolic pathways. These included nucleotide metabolism, urea cycle and arginine and proline metabolism. Silencing of identified proline metabolic and catabolic enzymes indicated that altered proline metabolism serves as an adaptive, rather than a toxic response. A group of enriched metabolic pathways clustered around the metabolite S-adenosylmethionine, which is a hub for methylation and transsulfuration reactions and polyamine metabolism. Enzymes and metabolites with pro- or anti-oxidant functions were also enriched but enhanced levels of reactive oxygen species were not measured in cisplatin-treated ES cells. Lastly, a number of the differentially regulated metabolic enzymes were identified as target genes of the transcription factor p53, pointing to p53-mediated alterations in metabolism in response to genotoxic stress. Altogether, our findings reveal interconnecting metabolic pathways that are responsive to cisplatin and may serve as signaling modules in the DDR in pluripotent stem cells.Louise von StechowAinhoa Ruiz-AracamaBob van de WaterAd PeijnenburgErik DanenArjen LommenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 10, p e76476 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Louise von Stechow Ainhoa Ruiz-Aracama Bob van de Water Ad Peijnenburg Erik Danen Arjen Lommen Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.
description	The chemotherapeutic compound, cisplatin causes various kinds of DNA lesions but also triggers other pertubations, such as ER and oxidative stress. We and others have shown that treatment of pluripotent stem cells with cisplatin causes a plethora of transcriptional and post-translational alterations that, to a major extent, point to DNA damage response (DDR) signaling. The orchestrated DDR signaling network is important to arrest the cell cycle and repair the lesions or, in case of damage beyond repair, eliminate affected cells. Failure to properly balance the various aspects of the DDR in stem cells contributes to ageing and cancer. Here, we performed metabolic profiling by mass spectrometry of embryonic stem (ES) cells treated for different time periods with cisplatin. We then integrated metabolomics with transcriptomics analyses and connected cisplatin-regulated metabolites with regulated metabolic enzymes to identify enriched metabolic pathways. These included nucleotide metabolism, urea cycle and arginine and proline metabolism. Silencing of identified proline metabolic and catabolic enzymes indicated that altered proline metabolism serves as an adaptive, rather than a toxic response. A group of enriched metabolic pathways clustered around the metabolite S-adenosylmethionine, which is a hub for methylation and transsulfuration reactions and polyamine metabolism. Enzymes and metabolites with pro- or anti-oxidant functions were also enriched but enhanced levels of reactive oxygen species were not measured in cisplatin-treated ES cells. Lastly, a number of the differentially regulated metabolic enzymes were identified as target genes of the transcription factor p53, pointing to p53-mediated alterations in metabolism in response to genotoxic stress. Altogether, our findings reveal interconnecting metabolic pathways that are responsive to cisplatin and may serve as signaling modules in the DDR in pluripotent stem cells.
format	article
author	Louise von Stechow Ainhoa Ruiz-Aracama Bob van de Water Ad Peijnenburg Erik Danen Arjen Lommen
author_facet	Louise von Stechow Ainhoa Ruiz-Aracama Bob van de Water Ad Peijnenburg Erik Danen Arjen Lommen
author_sort	Louise von Stechow
title	Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.
title_short	Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.
title_full	Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.
title_fullStr	Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.
title_full_unstemmed	Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.
title_sort	identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/790b6b9894b74c379669e034e7c6175f
work_keys_str_mv	AT louisevonstechow identificationofcisplatinregulatedmetabolicpathwaysinpluripotentstemcells AT ainhoaruizaracama identificationofcisplatinregulatedmetabolicpathwaysinpluripotentstemcells AT bobvandewater identificationofcisplatinregulatedmetabolicpathwaysinpluripotentstemcells AT adpeijnenburg identificationofcisplatinregulatedmetabolicpathwaysinpluripotentstemcells AT erikdanen identificationofcisplatinregulatedmetabolicpathwaysinpluripotentstemcells AT arjenlommen identificationofcisplatinregulatedmetabolicpathwaysinpluripotentstemcells
_version_	1718421270357344256

Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.

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