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.