Targeting Fatty Acid Synthase Modulates Metabolic Pathways and Inhibits Cholangiocarcinoma Cell Progression

Abstract

An aberrant regulation of lipid metabolism is involved in the pathogenesis and progression of cancer. Up-regulation of lipid biosynthesis enzymes, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN) and HMG-CoA reductase (HMGCR), has been reported in many cancers. Therefore, elucidating lipid metabolism changes in cancer is essential for the development of novel therapeutic targets for various human cancers. The current study aimed to identify the abnormal expression of lipid-metabolizing enzymes in cholangiocarcinoma (CCA) and to evaluate whether they can be used as the targets for CCA treatment. Our study demonstrated that a high expression of FASN was significantly correlated with the advanced stage in CCA patients. In addition, survival analysis showed that high expression of FASN and HMGCR was correlated with shorter survival of CCA patients. Furthermore, FASN knockdown inhibited the growth, migration and invasion in CCA cell lines, KKU055 and KKU213, as well as induced cell cycle arrest and apoptosis in the CCA cell lines. In addition, metabolomics study further revealed that purine metabolism was the most relevant pathway involved in FASN knockdown. Adenosine diphosphate (ADP), glutamine and guanine levels significantly increased in KKU213 cells while guanine and xanthine levels remarkably increased in KKU055 cells showing a marked difference between the control and FASN knockdown groups. These findings provide new insights into the mechanisms associated with FASN knockdown in CCA cell lines and suggest that targeting FASN may serve as a novel CCA therapeutic strategy.

Metabolic reprogramming in cholangiocarcinoma

“…Metabolomic studies showed that purine metabolism was the most relevant pathway involved in FASN knockdown. 77 Accordingly, FASN was found to be repressed by lysine demethylase 5C during iCCA progression and lysine demethylase 5C downregulation was associated with poor prognosis in iCCA. 78 A possible explanation for the differential results regarding the role of FASN may be the different availability of FAs in the cellular context and extracellular microenvironment.…”

“…74 In contrast, other studies showed that FASN expression was directly correlated with advanced stage CCA and was associated with shorter survival in a database of 155 patients. 77 Furthermore, FASN knockdown inhibited growth, migration, invasion and cell cycle progression, and induced apoptosis in CCA cells. Metabolomic studies showed that purine metabolism was the most relevant pathway involved in FASN knockdown.…”

Lipid alterations in chronic liver disease and liver cancer

“…In addition to FA synthesis, other lipogenesis pathways have also been demonstrated to be deregulated during HCC development. The rate-limiting enzyme of cholesterol synthesis (and target of statins) 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) is upregulated in HCC 246 and CCA 247 and thus, the use of statins is associated with reduced risk of liver cancer development. 143 , 248 Furthermore, increased expression of squalene epoxidase 249 has been implicated in the development of NAFLD-HCC.…”

New insights into the pathological development of dyslipidemia in patients with hypothyroidism

“…Alterations of ACC/FAS could promote the risk and the development of dyslipidemia and its related cardio-metabolic disorder diseases [32]. Recently, the important roles of thyroid hormones in regulating the metabolism of ACC/FAS have begun to gain appreciation.…”