Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.

<h4>Background</h4>An important phenomenon observed in glioma metabolism is increased aerobic glycolysis in tumor cells, which is generally referred to as the Warburg effect. Transforming growth factor (TGF)-beta2, which we previously showed to be induced by lactic acid, is a key pathoph...

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Autores principales:	Corinna Seliger, Petra Leukel, Sylvia Moeckel, Birgit Jachnik, Claudio Lottaz, Marina Kreutz, Alexander Brawanski, Martin Proescholdt, Ulrich Bogdahn, Anja-Katrin Bosserhoff, Arabel Vollmann-Zwerenz, Peter Hau
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1fc17143c8934f4391c9940b5b56f307
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spelling	oai:doaj.org-article:1fc17143c8934f4391c9940b5b56f3072021-11-18T08:48:44ZLactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.1932-620310.1371/journal.pone.0078935https://doaj.org/article/1fc17143c8934f4391c9940b5b56f3072013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24223867/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>An important phenomenon observed in glioma metabolism is increased aerobic glycolysis in tumor cells, which is generally referred to as the Warburg effect. Transforming growth factor (TGF)-beta2, which we previously showed to be induced by lactic acid, is a key pathophysiological factor in glioblastoma, leading to increased invasion and severe local immunosuppression after proteolytic cleavage from its latency associated peptide. In this study we tested the hypothesis, that lactate regulates TGF-beta2 expression and glioma cell migration via induction of Thrombospondin-1 (THBS-1), a TGF-beta activating protein.<h4>Methods</h4>Lactate levels were reduced by knockdown of LDH-A using specific small interfering RNA (siRNA) and competitive inhibition of LDH-A by sodium oxamate. Knockdown of THBS-1 was performed using specific siRNA. Western Blot, qRT-PCR, and ELISA were used to investigate expression levels of LDH-A, LDH-B, TGF-beta2 and THBS-1. Migration of cells was examined by Spheroid, Scratch and Boyden Chamber assays.<h4>Results</h4>Knockdown of LDH-A with subsequent decrease of lactate concentration leads to reduced levels of THBS-1 and TGF-beta2 in glioma cells. Lactate addition increases THBS-1 protein, leading to increased activation of TGF-beta2. Inhibition of THBS-1 reduces TGF-beta2 protein and migration of glioma cells. Addition of synthetic THBS-1 can rescue reduced TGF-beta2 protein levels and glioma cell migration in siLDH-A treated cells.<h4>Conclusion</h4>We define a regulatory cascade between lactate, THBS-1 and TGF-beta2, leading to enhanced migration of glioma cells. Our results demonstrate a specific interaction between tumor metabolism and migration and provide a better understanding of the mechanisms underlying glioma cell invasion.Corinna SeligerPetra LeukelSylvia MoeckelBirgit JachnikClaudio LottazMarina KreutzAlexander BrawanskiMartin ProescholdtUlrich BogdahnAnja-Katrin BosserhoffArabel Vollmann-ZwerenzPeter HauPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e78935 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Corinna Seliger Petra Leukel Sylvia Moeckel Birgit Jachnik Claudio Lottaz Marina Kreutz Alexander Brawanski Martin Proescholdt Ulrich Bogdahn Anja-Katrin Bosserhoff Arabel Vollmann-Zwerenz Peter Hau Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.
description	<h4>Background</h4>An important phenomenon observed in glioma metabolism is increased aerobic glycolysis in tumor cells, which is generally referred to as the Warburg effect. Transforming growth factor (TGF)-beta2, which we previously showed to be induced by lactic acid, is a key pathophysiological factor in glioblastoma, leading to increased invasion and severe local immunosuppression after proteolytic cleavage from its latency associated peptide. In this study we tested the hypothesis, that lactate regulates TGF-beta2 expression and glioma cell migration via induction of Thrombospondin-1 (THBS-1), a TGF-beta activating protein.<h4>Methods</h4>Lactate levels were reduced by knockdown of LDH-A using specific small interfering RNA (siRNA) and competitive inhibition of LDH-A by sodium oxamate. Knockdown of THBS-1 was performed using specific siRNA. Western Blot, qRT-PCR, and ELISA were used to investigate expression levels of LDH-A, LDH-B, TGF-beta2 and THBS-1. Migration of cells was examined by Spheroid, Scratch and Boyden Chamber assays.<h4>Results</h4>Knockdown of LDH-A with subsequent decrease of lactate concentration leads to reduced levels of THBS-1 and TGF-beta2 in glioma cells. Lactate addition increases THBS-1 protein, leading to increased activation of TGF-beta2. Inhibition of THBS-1 reduces TGF-beta2 protein and migration of glioma cells. Addition of synthetic THBS-1 can rescue reduced TGF-beta2 protein levels and glioma cell migration in siLDH-A treated cells.<h4>Conclusion</h4>We define a regulatory cascade between lactate, THBS-1 and TGF-beta2, leading to enhanced migration of glioma cells. Our results demonstrate a specific interaction between tumor metabolism and migration and provide a better understanding of the mechanisms underlying glioma cell invasion.
format	article
author	Corinna Seliger Petra Leukel Sylvia Moeckel Birgit Jachnik Claudio Lottaz Marina Kreutz Alexander Brawanski Martin Proescholdt Ulrich Bogdahn Anja-Katrin Bosserhoff Arabel Vollmann-Zwerenz Peter Hau
author_facet	Corinna Seliger Petra Leukel Sylvia Moeckel Birgit Jachnik Claudio Lottaz Marina Kreutz Alexander Brawanski Martin Proescholdt Ulrich Bogdahn Anja-Katrin Bosserhoff Arabel Vollmann-Zwerenz Peter Hau
author_sort	Corinna Seliger
title	Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.
title_short	Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.
title_full	Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.
title_fullStr	Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.
title_full_unstemmed	Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.
title_sort	lactate-modulated induction of thbs-1 activates transforming growth factor (tgf)-beta2 and migration of glioma cells in vitro.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/1fc17143c8934f4391c9940b5b56f307
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Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.

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