Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2
BackgroundMetabolic reprogramming has emerged as a cancer hallmark, and one of the well-known cancer-associated metabolic alterations is the increase in the rate of glycolysis. Recent reports have shown that both the classical and alternative signaling pathways of nuclear factor κB (NF-κB) play impo...
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doaj-454ae91c45e04e6990122e03d8a55e952020-11-24T22:01:59ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2018-04-01810.3389/fonc.2018.00104273145Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2Priya Londhe0Priya Londhe1Peter Y. Yu2Peter Y. Yu3Yuichi Ijiri4Yuichi Ijiri5Katherine J. Ladner6Katherine J. Ladner7Joelle M. Fenger8Cheryl London9Cheryl London10Peter J. Houghton11Denis C. Guttridge12Denis C. Guttridge13Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United StatesArthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United StatesArthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United StatesMedical Student Research Program, The Ohio State University, Columbus, OH, United StatesDepartment of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United StatesArthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United StatesDepartment of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United StatesArthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United StatesDepartment of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, United StatesDepartment of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, United StatesCummings School of Veterinary Medicine, Tufts University, Grafton, MA, United StatesGreehey Children’s Research Institute, University of Texas Health Science Center, San Antonio, TX, United StatesDepartment of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United StatesArthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United StatesBackgroundMetabolic reprogramming has emerged as a cancer hallmark, and one of the well-known cancer-associated metabolic alterations is the increase in the rate of glycolysis. Recent reports have shown that both the classical and alternative signaling pathways of nuclear factor κB (NF-κB) play important roles in controlling the metabolic profiles of normal cells and cancer cells. However, how these signaling pathways affect the metabolism of sarcomas, specifically rhabdomyosarcoma (RMS) and osteosarcoma (OS), has not been characterized.MethodsClassical NF-κB activity was inhibited through overexpression of the IκBα super repressor of NF-κB in RMS and OS cells. Global gene expression analysis was performed using Affymetrix GeneChip Human Transcriptome Array 2.0, and data were interpreted using gene set enrichment analysis. Seahorse Bioscience XFe24 was used to analyze oxygen consumption rate as a measure of aerobic respiration.ResultsInhibition of classical NF-κB activity in sarcoma cell lines restored alternative signaling as well as an increased oxidative respiratory metabolic phenotype in vitro. In addition, microarray analysis indicated that inhibition of NF-κB in sarcoma cells reduced glycolysis. We showed that a glycolytic gene, hexokinase (HK) 2, is a direct NF-κB transcriptional target. Knockdown of HK2 shifted the metabolic profile in sarcoma cells away from aerobic glycolysis, and re-expression of HK2 rescued the metabolic shift induced by inhibition of NF-κB activity in OS cells.ConclusionThese findings suggest that classical signaling of NF-κB plays a crucial role in the metabolic profile of pediatric sarcomas potentially through the regulation of HK2.http://journal.frontiersin.org/article/10.3389/fonc.2018.00104/fullsarcomanuclear factor kappa Bmetabolismhexokinaserhabdomyosarcomaosteosarcoma |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Priya Londhe Priya Londhe Peter Y. Yu Peter Y. Yu Yuichi Ijiri Yuichi Ijiri Katherine J. Ladner Katherine J. Ladner Joelle M. Fenger Cheryl London Cheryl London Peter J. Houghton Denis C. Guttridge Denis C. Guttridge |
spellingShingle |
Priya Londhe Priya Londhe Peter Y. Yu Peter Y. Yu Yuichi Ijiri Yuichi Ijiri Katherine J. Ladner Katherine J. Ladner Joelle M. Fenger Cheryl London Cheryl London Peter J. Houghton Denis C. Guttridge Denis C. Guttridge Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2 Frontiers in Oncology sarcoma nuclear factor kappa B metabolism hexokinase rhabdomyosarcoma osteosarcoma |
author_facet |
Priya Londhe Priya Londhe Peter Y. Yu Peter Y. Yu Yuichi Ijiri Yuichi Ijiri Katherine J. Ladner Katherine J. Ladner Joelle M. Fenger Cheryl London Cheryl London Peter J. Houghton Denis C. Guttridge Denis C. Guttridge |
author_sort |
Priya Londhe |
title |
Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2 |
title_short |
Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2 |
title_full |
Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2 |
title_fullStr |
Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2 |
title_full_unstemmed |
Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2 |
title_sort |
classical nf-κb metabolically reprograms sarcoma cells through regulation of hexokinase 2 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2018-04-01 |
description |
BackgroundMetabolic reprogramming has emerged as a cancer hallmark, and one of the well-known cancer-associated metabolic alterations is the increase in the rate of glycolysis. Recent reports have shown that both the classical and alternative signaling pathways of nuclear factor κB (NF-κB) play important roles in controlling the metabolic profiles of normal cells and cancer cells. However, how these signaling pathways affect the metabolism of sarcomas, specifically rhabdomyosarcoma (RMS) and osteosarcoma (OS), has not been characterized.MethodsClassical NF-κB activity was inhibited through overexpression of the IκBα super repressor of NF-κB in RMS and OS cells. Global gene expression analysis was performed using Affymetrix GeneChip Human Transcriptome Array 2.0, and data were interpreted using gene set enrichment analysis. Seahorse Bioscience XFe24 was used to analyze oxygen consumption rate as a measure of aerobic respiration.ResultsInhibition of classical NF-κB activity in sarcoma cell lines restored alternative signaling as well as an increased oxidative respiratory metabolic phenotype in vitro. In addition, microarray analysis indicated that inhibition of NF-κB in sarcoma cells reduced glycolysis. We showed that a glycolytic gene, hexokinase (HK) 2, is a direct NF-κB transcriptional target. Knockdown of HK2 shifted the metabolic profile in sarcoma cells away from aerobic glycolysis, and re-expression of HK2 rescued the metabolic shift induced by inhibition of NF-κB activity in OS cells.ConclusionThese findings suggest that classical signaling of NF-κB plays a crucial role in the metabolic profile of pediatric sarcomas potentially through the regulation of HK2. |
topic |
sarcoma nuclear factor kappa B metabolism hexokinase rhabdomyosarcoma osteosarcoma |
url |
http://journal.frontiersin.org/article/10.3389/fonc.2018.00104/full |
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