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Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer
BACKGROUND: Loss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. However, metabolic differences between isogenic cells with and without HSulf-1 have not been characterized upon HSulf-1 suppr...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164348/ https://www.ncbi.nlm.nih.gov/pubmed/25225614 http://dx.doi.org/10.1186/2049-3002-2-13 |
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author | Roy, Debarshi Mondal, Susmita Wang, Chen He, Xiaoping Khurana, Ashwani Giri, Shailendra Hoffmann, Robert Jung, Deok-Beom Kim, Sung H Chini, Eduardo N Periera, Juliana Camacho Folmes, Clifford D Mariani, Andrea Dowdy, Sean C Bakkum-Gamez, Jamie N Riska, Shaun M Oberg, Ann L Karoly, Edward D Bell, Lauren N Chien, Jeremy Shridhar, Viji |
author_facet | Roy, Debarshi Mondal, Susmita Wang, Chen He, Xiaoping Khurana, Ashwani Giri, Shailendra Hoffmann, Robert Jung, Deok-Beom Kim, Sung H Chini, Eduardo N Periera, Juliana Camacho Folmes, Clifford D Mariani, Andrea Dowdy, Sean C Bakkum-Gamez, Jamie N Riska, Shaun M Oberg, Ann L Karoly, Edward D Bell, Lauren N Chien, Jeremy Shridhar, Viji |
author_sort | Roy, Debarshi |
collection | PubMed |
description | BACKGROUND: Loss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. However, metabolic differences between isogenic cells with and without HSulf-1 have not been characterized upon HSulf-1 suppression in vitro. Since growth factor signaling is closely tied to metabolic alterations, we determined the extent to which HSulf-1 loss affects cancer cell metabolism. RESULTS: Ingenuity pathway analysis of gene expression in HSulf-1 shRNA-silenced cells (Sh1 and Sh2 cells) compared to non-targeted control shRNA cells (NTC cells) and subsequent Kyoto Encyclopedia of Genes and Genomics (KEGG) database analysis showed altered metabolic pathways with changes in the lipid metabolism as one of the major pathways altered inSh1 and 2 cells. Untargeted global metabolomic profiling in these isogenic cell lines identified approximately 338 metabolites using GC/MS and LC/MS/MS platforms. Knockdown of HSulf-1 in OV202 cells induced significant changes in 156 metabolites associated with several metabolic pathways including amino acid, lipids, and nucleotides. Loss of HSulf-1 promoted overall fatty acid synthesis leading to enhance the metabolite levels of long chain, branched, and essential fatty acids along with sphingolipids. Furthermore, HSulf-1 loss induced the expression of lipogenic genes including FASN, SREBF1, PPARγ, and PLA2G3 stimulated lipid droplet accumulation. Conversely, re-expression of HSulf-1 in Sh1 cells reduced the lipid droplet formation. Additionally, HSulf-1 also enhanced CPT1A and fatty acid oxidation and augmented the protein expression of key lipolytic enzymes such as MAGL, DAGLA, HSL, and ASCL1. Overall, these findings suggest that loss of HSulf-1 by concomitantly enhancing fatty acid synthesis and oxidation confers a lipogenic phenotype leading to the metabolic alterations associated with the progression of ovarian cancer. CONCLUSIONS: Taken together, these findings demonstrate that loss of HSulf-1 potentially contributes to the metabolic alterations associated with the progression of ovarian pathogenesis, specifically impacting the lipogenic phenotype of ovarian cancer cells that can be therapeutically targeted. |
format | Online Article Text |
id | pubmed-4164348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-41643482014-09-16 Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer Roy, Debarshi Mondal, Susmita Wang, Chen He, Xiaoping Khurana, Ashwani Giri, Shailendra Hoffmann, Robert Jung, Deok-Beom Kim, Sung H Chini, Eduardo N Periera, Juliana Camacho Folmes, Clifford D Mariani, Andrea Dowdy, Sean C Bakkum-Gamez, Jamie N Riska, Shaun M Oberg, Ann L Karoly, Edward D Bell, Lauren N Chien, Jeremy Shridhar, Viji Cancer Metab Research BACKGROUND: Loss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. However, metabolic differences between isogenic cells with and without HSulf-1 have not been characterized upon HSulf-1 suppression in vitro. Since growth factor signaling is closely tied to metabolic alterations, we determined the extent to which HSulf-1 loss affects cancer cell metabolism. RESULTS: Ingenuity pathway analysis of gene expression in HSulf-1 shRNA-silenced cells (Sh1 and Sh2 cells) compared to non-targeted control shRNA cells (NTC cells) and subsequent Kyoto Encyclopedia of Genes and Genomics (KEGG) database analysis showed altered metabolic pathways with changes in the lipid metabolism as one of the major pathways altered inSh1 and 2 cells. Untargeted global metabolomic profiling in these isogenic cell lines identified approximately 338 metabolites using GC/MS and LC/MS/MS platforms. Knockdown of HSulf-1 in OV202 cells induced significant changes in 156 metabolites associated with several metabolic pathways including amino acid, lipids, and nucleotides. Loss of HSulf-1 promoted overall fatty acid synthesis leading to enhance the metabolite levels of long chain, branched, and essential fatty acids along with sphingolipids. Furthermore, HSulf-1 loss induced the expression of lipogenic genes including FASN, SREBF1, PPARγ, and PLA2G3 stimulated lipid droplet accumulation. Conversely, re-expression of HSulf-1 in Sh1 cells reduced the lipid droplet formation. Additionally, HSulf-1 also enhanced CPT1A and fatty acid oxidation and augmented the protein expression of key lipolytic enzymes such as MAGL, DAGLA, HSL, and ASCL1. Overall, these findings suggest that loss of HSulf-1 by concomitantly enhancing fatty acid synthesis and oxidation confers a lipogenic phenotype leading to the metabolic alterations associated with the progression of ovarian cancer. CONCLUSIONS: Taken together, these findings demonstrate that loss of HSulf-1 potentially contributes to the metabolic alterations associated with the progression of ovarian pathogenesis, specifically impacting the lipogenic phenotype of ovarian cancer cells that can be therapeutically targeted. BioMed Central 2014-08-18 /pmc/articles/PMC4164348/ /pubmed/25225614 http://dx.doi.org/10.1186/2049-3002-2-13 Text en Copyright © 2014 Roy et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Roy, Debarshi Mondal, Susmita Wang, Chen He, Xiaoping Khurana, Ashwani Giri, Shailendra Hoffmann, Robert Jung, Deok-Beom Kim, Sung H Chini, Eduardo N Periera, Juliana Camacho Folmes, Clifford D Mariani, Andrea Dowdy, Sean C Bakkum-Gamez, Jamie N Riska, Shaun M Oberg, Ann L Karoly, Edward D Bell, Lauren N Chien, Jeremy Shridhar, Viji Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer |
title | Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer |
title_full | Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer |
title_fullStr | Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer |
title_full_unstemmed | Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer |
title_short | Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer |
title_sort | loss of hsulf-1 promotes altered lipid metabolism in ovarian cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164348/ https://www.ncbi.nlm.nih.gov/pubmed/25225614 http://dx.doi.org/10.1186/2049-3002-2-13 |
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