Citrate Synthase Expression Affects Tumor Phenotype and Drug Resistance in Human Ovarian Carcinoma

Abstract

Citrate synthase (CS), one of the key enzymes in the tricarboxylic acid (TCA) cycle, catalyzes the reaction between oxaloacetic acid and acetyl coenzyme A to generate citrate. Increased CS has been observed in pancreatic cancer. In this study, we found higher CS expression in malignant ovarian tumors and ovarian cancer cell lines compared to benign ovarian tumors and normal human ovarian surface epithelium, respectively. CS knockdown by RNAi could result in the reduction of cell proliferation, and inhibition of invasion and migration of ovarian cancer cells in vitro. The drug resistance was also inhibited possibly through an excision repair cross complementing 1 (ERCC1)-dependent mechanism. Finally, upon CS knockdown we observed significant increase expression of multiple genes, including ISG15, IRF7, CASP7, and DDX58 in SKOV3 and A2780 cells by microarray analysis and real-time PCR. Taken together, these results suggested that CS might represent a potential therapeutic target for ovarian carcinoma.

Global metabolomic profiling of trastuzumab resistant gastric cancer cells reveals major metabolic pathways and metabolic signatures based on UHPLC-Q exactive-MS/MS

“…A growing body of evidence indicate that high levels of CS is closely associated with tumor metastasis, proliferation and drug resistance by increasing ATP synthesis which contribute to cell proliferation and drug resistance. 28,29 Consistent with these studies, our results from proteomics data displayed that CS was upregulated in trastuzumab resistant cells compared with parental cells, suggesting its contribution to trastuzumab resistance. ACLY, another key cytosolic enzyme, catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA, the latter serving as common substrate for de novo lipogenesis.…”

Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

“…Citrate plays a critical role in the fatty acid synthesis, where it can be used in the production of acetyl groups [51], consequently suggesting that fatty acid synthesis can be a potential target of METi. The TCA cycle and ETC have a balanced partnership-they each lean on the other to function properly and a reduction of citrate synthase can potentially affect the flow of cellular respiration followed by tumor growth attenuation, inhibition of invasion, migration and upregulation of glycolysis in MET-overexpressing tumors as was shown previously in ovarian carcinoma with increased citrate synthase activity [52]. Interestingly, the activity of citrate synthase was higher in unperturbed Y1248H compared to M1268T, indicating that there is a difference in mitochondrial abundance between the two cell lines, most possibly caused by different metabolic profiles of these isogenic cell lines and their different intensity of downstream signals (Fig.…”

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

“…This is the first step and the rate-limiting reaction of the TCA cycle [66]. CS presents either up-regulation or increased enzymatic activity in various cancer types such as ovarian and pancreatic cancer [67,68]. Noteworthy, CS enzyme activity has been reported to be increased in HCC [69].…”