Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells

Abstract Accumulating evidences suggest that p53 is a key coordinator of cellular events triggered by oxidative stress often associated with the impairment in thiamine metabolism and its functions. However, there are limited data regarding the pursuant feedback between p53 transactivation and thiami...

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Autores principales:	Sergiy Chornyy, Yulia Parkhomenko, Nataliya Chorna
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d66a2e5e989a4fa0a3b84b686578c8b6
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spelling	oai:doaj.org-article:d66a2e5e989a4fa0a3b84b686578c8b62021-12-02T15:04:54ZThiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells10.1038/s41598-017-10878-x2045-2322https://doaj.org/article/d66a2e5e989a4fa0a3b84b686578c8b62017-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-10878-xhttps://doaj.org/toc/2045-2322Abstract Accumulating evidences suggest that p53 is a key coordinator of cellular events triggered by oxidative stress often associated with the impairment in thiamine metabolism and its functions. However, there are limited data regarding the pursuant feedback between p53 transactivation and thiamine homeostasis. Impairment in thiamine metabolism can be induced experimentally via interference with the thiamine uptake and/or inhibition of the thiamin pyrophosphate–dependent enzymes using thiamine antagonists - amprolium (AM), oxythiamine (OT) or pyrithiamine (PT). We found that exposure of neuronally differentiated SH-SY5Y cells to AM, OT and PT triggered upregulation of p53 gene expression, post-translational modification of p53 via phosphorylation and activation of p53 DNA-binding activity. Phosphorylation of p53 at Ser20 was equally efficient in upregulation of thiamine transporter 1 (THTR1) by all antagonists. However, induction of the expressions of the pyruvate dehydrogenase E1 component subunit beta (PDHB) and oxoglutarate dehydrogenase (OGDH) required dual phosphorylation of p53 at Ser9 and Ser20, seen in cells treated with PT and OT. Moreover, pretreatment of the cells with a decoy oligonucleotide carrying wild-type p53-response element markedly attenuated OT-induced THTR1, PDHB and OGDH gene expression suggesting an important role of p53 in transactivation of these genes. Finally, analysis of gene and metabolic networks showed that OT triggers cell apoptosis through the p53-dependent intrinsic pathway.Sergiy ChornyyYulia ParkhomenkoNataliya ChornaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sergiy Chornyy Yulia Parkhomenko Nataliya Chorna Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells
description	Abstract Accumulating evidences suggest that p53 is a key coordinator of cellular events triggered by oxidative stress often associated with the impairment in thiamine metabolism and its functions. However, there are limited data regarding the pursuant feedback between p53 transactivation and thiamine homeostasis. Impairment in thiamine metabolism can be induced experimentally via interference with the thiamine uptake and/or inhibition of the thiamin pyrophosphate–dependent enzymes using thiamine antagonists - amprolium (AM), oxythiamine (OT) or pyrithiamine (PT). We found that exposure of neuronally differentiated SH-SY5Y cells to AM, OT and PT triggered upregulation of p53 gene expression, post-translational modification of p53 via phosphorylation and activation of p53 DNA-binding activity. Phosphorylation of p53 at Ser20 was equally efficient in upregulation of thiamine transporter 1 (THTR1) by all antagonists. However, induction of the expressions of the pyruvate dehydrogenase E1 component subunit beta (PDHB) and oxoglutarate dehydrogenase (OGDH) required dual phosphorylation of p53 at Ser9 and Ser20, seen in cells treated with PT and OT. Moreover, pretreatment of the cells with a decoy oligonucleotide carrying wild-type p53-response element markedly attenuated OT-induced THTR1, PDHB and OGDH gene expression suggesting an important role of p53 in transactivation of these genes. Finally, analysis of gene and metabolic networks showed that OT triggers cell apoptosis through the p53-dependent intrinsic pathway.
format	article
author	Sergiy Chornyy Yulia Parkhomenko Nataliya Chorna
author_facet	Sergiy Chornyy Yulia Parkhomenko Nataliya Chorna
author_sort	Sergiy Chornyy
title	Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells
title_short	Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells
title_full	Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells
title_fullStr	Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells
title_full_unstemmed	Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells
title_sort	thiamine antagonists trigger p53-dependent apoptosis in differentiated sh-sy5y cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d66a2e5e989a4fa0a3b84b686578c8b6
work_keys_str_mv	AT sergiychornyy thiamineantagoniststriggerp53dependentapoptosisindifferentiatedshsy5ycells AT yuliaparkhomenko thiamineantagoniststriggerp53dependentapoptosisindifferentiatedshsy5ycells AT nataliyachorna thiamineantagoniststriggerp53dependentapoptosisindifferentiatedshsy5ycells
_version_	1718389047033856000

Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells

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