Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer.
Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer.
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DOI：
10.1186/2049-3002-2-13
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发表时间：
2014
影响因子：
5.9
通讯作者：
Shridhar V
中科院分区：
文献类型：
--
作者：
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
内源性硫酸酯酶HSulf-1的缺失在卵巢癌中很常见，它能上调肝素结合生长因子信号并促进肿瘤发生和血管生成。然而，在体外HSulf-1抑制的情况下，HSulf-1与不含HSulf-1的等基因细胞之间的代谢差异尚未被表征。由于生长因子信号传导与代谢改变密切相关，我们确定了HSulf-1缺失对癌细胞代谢的影响程度。与非靶向对照shRNA细胞（NTC细胞）相比，HSulf-1 shRNA沉默细胞（Sh1和Sh2细胞）的基因表达的Ingenuity通路分析以及随后的京都基因与基因组学百科全书（KEGG）数据库分析显示，代谢途径发生了改变，脂质代谢的改变是Sh1和2细胞改变的主要途径之一。利用GC/MS和LC/MS/MS平台对这些等基因细胞系进行非靶向全球代谢组学分析，鉴定出大约338种代谢物。OV202细胞中HSulf-1的敲低诱导156种代谢物的显著变化，这些代谢物与几种代谢途径相关，包括氨基酸、脂质和核苷酸。HSulf-1的缺失促进了整体脂肪酸的合成，导致长链、支链和必需脂肪酸以及鞘脂的代谢产物水平升高。此外，HSulf-1缺失诱导脂肪生成基因FASN、SREBF1、PPARγ和PLA2G3的表达，刺激脂滴积累。相反，在Sh1细胞中重新表达HSulf-1会减少脂滴的形成。此外，HSulf-1还增强了CPT1A和脂肪酸氧化，并增加了关键脂溶酶如MAGL、DAGLA、HSL和ASCL1的蛋白表达。总的来说，这些发现表明，通过同时增强脂肪酸合成和氧化，HSulf-1的缺失会导致脂肪生成表型，从而导致与卵巢癌进展相关的代谢改变。综上所述，这些发现表明，HSulf-1的缺失可能会导致与卵巢发病机制进展相关的代谢改变，特别是影响卵巢癌细胞的脂肪生成表型，这可以作为治疗靶点。
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. 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. 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.