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

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

doi:10.1186/2049-3002-2-13

Abstract

BackgroundLoss 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.ResultsIngenuity 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.ConclusionsTaken 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.

Highlights

Loss of the endosulfatase Human Sulfatase 1 (HSulf-1) is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis
Ingenuity pathway analysis for these genes showed that most genes were differentially regulated in the fatty acid/lipid pathways in Sh1 and Sh2 cells compared to NTC cells (Additional file 2: Table S1, Figure 1B)
We explored the 271 genes in the lipid related pathways from our microarray data by unsupervised clustering (Figure 1C) and found that 26% (73 of 271) genes were differentially expressed in Sh1 and Sh2 cells compared to NTC cells (Figure 1D), indicating that tumor suppressor HSulf-1 possibly regulates the lipid metabolism in ovarian cancer cells

Summary

Introduction

Loss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. Since growth factor signaling is closely tied to metabolic alterations, we determined the extent to which HSulf-1 loss affects cancer cell metabolism. Alteration of cellular metabolism in cancer cells is proposed to increase the availability of essential building blocks that support uncontrolled cellular proliferation [1]. Alterations in fatty acids (FAs) and lipid metabolism have received less attention, recently, their importance in cancer metabolism is being increasingly recognized. The total lipid pools required for membrane synthesis of dividing cells are derived mainly from FAs and in part from acetyl CoA [4] Cancer cells meet their FAs demand mainly by increasing de novo FA synthesis rather than from exogenous sources and partly from acetyl CoA [5,6]. The rest of the activated FAs function as signaling molecules or esterified as triglycerols or sterol esters and stored in lipid droplets (LDs) [7,8]

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