Low intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells

Elizabeth Tahanian, Sabrina Peiro, Borhane AnnabiLaboratoire d&#39;Oncologie Mol&eacute;culaire, Centre de Recherche BioMED, D&eacute;partement de Chimie, Universit&eacute; du Qu&eacute;bec &agrave; Montr&eacute;al, Montr&eacute;al, Qu&...

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Autores principales:	Elizabeth Tahanian, Sabrina Peiro, Borhane Annabi
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2011
Materias:	Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/71941ecdd5fa430097fa9c6e3db41148
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spelling	oai:doaj.org-article:71941ecdd5fa430097fa9c6e3db411482021-12-02T07:42:38ZLow intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells1178-7031https://doaj.org/article/71941ecdd5fa430097fa9c6e3db411482011-01-01T00:00:00Zhttp://www.dovepress.com/low-intracellular-atp-levels-exacerbate-carcinogen-induced-inflammator-a6017https://doaj.org/toc/1178-7031Elizabeth Tahanian, Sabrina Peiro, Borhane AnnabiLaboratoire d&#39;Oncologie Mol&eacute;culaire, Centre de Recherche BioMED, D&eacute;partement de Chimie, Universit&eacute; du Qu&eacute;bec &agrave; Montr&eacute;al, Montr&eacute;al, Qu&eacute;bec, CanadaAbstract: Solid tumor development requires angiogenesis and is correlated to the expression of inflammatory markers through cellular metabolic and energetic adaptation. While high glycolysis rates enable the cancer cell compartment to generate adenosine triphosphate (ATP), very little is known about the impact of low intracellular ATP concentrations within the vascular endothelial cell compartment, which is responsible for tumor angiogenesis. Here, we investigated the effect of 2-deoxy-D-glucose (2-DG), a glucose analog that inhibits glycolysis through intracellular ATP depletion, on human brain microvascular endothelial cell (HBMEC) angiogenic properties. While preformed capillaries remained unaffected, we found that in vitro tubulogenesis was dose-dependently decreased by 2-DG and that this correlated with reduced intracellular ATP levels. Procarcinogenic signaling was induced with phorbol 12-myristate 13-acetate (PMA) and found to trigger the proinflammatory marker cyclooxygenase-2 (COX-2) and endoplasmic reticulum (ER) stress marker GRP78 expression, whose inductions were potentiated when PMA was combined with 2-DG treatment. Inversely, PMA-induced matrix-metalloproteinase-9 (MMP-9) gene expression and protein secretion were abrogated in the presence of 2-DG, and this can be partially explained by reduced nuclear factor-&kappa;B signaling. Collectively, we provide evidence for an intracellular ATP requirement in order for tubulogenesis to occur, and we link increases in ER stress to inflammation. A better understanding of the metabolic adaptations of the vascular endothelial cells that mediate tumor vascularization will help the development of new drugs and therapies.Keywords: endoplasmic reticulum stress, MMP-9, COX-2, 2-deoxy-D-glucose, endothelial cells Elizabeth TahanianSabrina PeiroBorhane AnnabiDove Medical PressarticlePathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol 2011, Iss default, Pp 1-10 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Elizabeth Tahanian Sabrina Peiro Borhane Annabi Low intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells
description	Elizabeth Tahanian, Sabrina Peiro, Borhane AnnabiLaboratoire d&#39;Oncologie Mol&eacute;culaire, Centre de Recherche BioMED, D&eacute;partement de Chimie, Universit&eacute; du Qu&eacute;bec &agrave; Montr&eacute;al, Montr&eacute;al, Qu&eacute;bec, CanadaAbstract: Solid tumor development requires angiogenesis and is correlated to the expression of inflammatory markers through cellular metabolic and energetic adaptation. While high glycolysis rates enable the cancer cell compartment to generate adenosine triphosphate (ATP), very little is known about the impact of low intracellular ATP concentrations within the vascular endothelial cell compartment, which is responsible for tumor angiogenesis. Here, we investigated the effect of 2-deoxy-D-glucose (2-DG), a glucose analog that inhibits glycolysis through intracellular ATP depletion, on human brain microvascular endothelial cell (HBMEC) angiogenic properties. While preformed capillaries remained unaffected, we found that in vitro tubulogenesis was dose-dependently decreased by 2-DG and that this correlated with reduced intracellular ATP levels. Procarcinogenic signaling was induced with phorbol 12-myristate 13-acetate (PMA) and found to trigger the proinflammatory marker cyclooxygenase-2 (COX-2) and endoplasmic reticulum (ER) stress marker GRP78 expression, whose inductions were potentiated when PMA was combined with 2-DG treatment. Inversely, PMA-induced matrix-metalloproteinase-9 (MMP-9) gene expression and protein secretion were abrogated in the presence of 2-DG, and this can be partially explained by reduced nuclear factor-&kappa;B signaling. Collectively, we provide evidence for an intracellular ATP requirement in order for tubulogenesis to occur, and we link increases in ER stress to inflammation. A better understanding of the metabolic adaptations of the vascular endothelial cells that mediate tumor vascularization will help the development of new drugs and therapies.Keywords: endoplasmic reticulum stress, MMP-9, COX-2, 2-deoxy-D-glucose, endothelial cells
format	article
author	Elizabeth Tahanian Sabrina Peiro Borhane Annabi
author_facet	Elizabeth Tahanian Sabrina Peiro Borhane Annabi
author_sort	Elizabeth Tahanian
title	Low intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells
title_short	Low intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells
title_full	Low intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells
title_fullStr	Low intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells
title_full_unstemmed	Low intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells
title_sort	low intracellular atp levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells
publisher	Dove Medical Press
publishDate	2011
url	https://doaj.org/article/71941ecdd5fa430097fa9c6e3db41148
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Low intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells

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