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Roy D, Mondal S, Wang C, et al. Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer. Cancer Metab. 2014;2:13doi: 10.1186/2049-3002-2-13.
Roy, D., Mondal, S., Wang, C., He, X., Khurana, A., Giri, S., Hoffmann, R., Jung, D. B., Kim, S. H., Chini, E. N., Periera, J. C., Folmes, C. D., Mariani, A., Dowdy, S. C., Bakkum-Gamez, J. N., Riska, S. M., Oberg, A. L., Karoly, E. D., Bell, L. N., Chien, J., & Shridhar, V. (2014). Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer. Cancer & metabolism, 213. https://doi.org/10.1186/2049-3002-2-13
Roy, Debarshi, et al. "Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer." Cancer & metabolism vol. 2 (2014): 13. doi: https://doi.org/10.1186/2049-3002-2-13
Roy D, Mondal S, Wang C, He X, Khurana A, Giri S, Hoffmann R, Jung DB, Kim SH, Chini EN, Periera JC, Folmes CD, Mariani A, Dowdy SC, Bakkum-Gamez JN, Riska SM, Oberg AL, Karoly ED, Bell LN, Chien J, Shridhar V. Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer. Cancer Metab. 2014 Aug 18;2:13. doi: 10.1186/2049-3002-2-13. eCollection 2014. PMID: 25225614; PMCID: PMC4164348.
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Cancer Metab. 2014 Aug 18;2:13. doi: 10.1186/2049-3002-2-13. eCollection 2014.

Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer.

Cancer & metabolism

Debarshi Roy, Susmita Mondal, Chen Wang, Xiaoping He, Ashwani Khurana, Shailendra Giri, Robert Hoffmann, Deok-Beom Jung, Sung H Kim, Eduardo N Chini, Juliana Camacho Periera, Clifford D Folmes, Andrea Mariani, Sean C Dowdy, Jamie N Bakkum-Gamez, Shaun M Riska, Ann L Oberg, Edward D Karoly, Lauren N Bell, Jeremy Chien, Viji Shridhar

Affiliations

  1. Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  2. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
  3. Henry Ford Health System, Detroit, MI 48202, USA.
  4. Cancer Preventive Material Development Research Center (CPMRC), College of Oriental Medicine, Kyunghee University, Seoul 130-701, Republic of Korea.
  5. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  6. Department of Cardiovascular Disease, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  7. Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  8. Metabolon, Inc, Durham, NC 27713, USA.
  9. Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KN 66160, USA.

PMID: 25225614 PMCID: PMC4164348 DOI: 10.1186/2049-3002-2-13

Abstract

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, PPARĪ³, 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.

Keywords: HSulf-1; Lipid droplets; Lipogenesis; Lipolysis; Microarray and metabolite profiling

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