Abstract
Long-chain fatty acyl CoA synthetases (ACSLs) activate fatty acids by CoA addition thus facilitating their intracellular metabolism. Dysregulated ACSL expression features in several cancers and can affect processes such as ferroptosis, fatty acid β-oxidation, prostaglandin biosynthesis, steroidogenesis and phospholipid acyl chain remodelling. Here we investigate long chain acyl-CoA synthetase 3 (ACSL3) and long chain acyl-CoA synthetase 4 (ACSL4) expression in liver malignancies. The expression and subcellular localisations of the ACSL3 and ACSL4 isoforms in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and hepatic metastases were assessed by immunohistochemical analyses of multiple tumour tissue arrays and by subcellular fractionation of cultured HepG2 cells. The expression of both enzymes was increased in HCC compared with normal liver. Expression of ACSL3 was similar in HCC and hepatic metastases but lower in healthy tissue. Increased ACSL3 expression distinguished HCC from CCA with a sensitivity of 87.2% and a specificity of 75%. ACSL4 expression was significantly greater in HCC than in all other tumours and distinguished HCC from normal liver tissue with a sensitivity of 93.8% and specificity of 93.6%. Combined ACSL3 and ACSL4 staining scores distinguished HCC from hepatic metastases with 80.1% sensitivity and 77.1% specificity. These enzymes had partially overlapping intracellular distributions, ACSL4 localised to the plasma membrane and both isoforms associated with lipid droplets and the endoplasmic reticulum (ER). In conclusion, analysis of ACSL3 and ACSL4 expression can distinguish different classes of hepatic tumours.
Highlights
Reprogramming of cellular energetics is a hallmark of cancer [1]
This study focuses on the expression and subcellular localisations of two long chain fatty acyl-CoA synthetase family members (ACSLs), long chain acyl-CoA synthetase 3 (ACSL3) and long chain acyl-CoA synthetase 4 (ACSL4), in hepatocellular carcinoma (HCC) cells
Expression of ACSL3 and ACSL4 in a hepatic tissue microarray. Immunohistochemical staining for both isoforms exhibited cytoplasmic membrane localisation patterns that tended to be more intense and extensive in HCC samples compared with normal liver tissue, CCA or hepatic metastases (Figure 1)
Summary
Reprogramming of cellular energetics is a hallmark of cancer [1]. Alterations in lipid metabolism are frequently observed during tumour progression and acquired drug resistance [2,3]. Upregulation of fatty acid metabolism can promote cancer survival and proliferation by: (i) providing an alternative to glucose for ATP generation through β-oxidation [4,5,6] and (ii) driving phospholipid anabolism which is required for increased membrane biosynthesis and oncoprotein-induced cell signalling pathways [7,8,9,10]. This study focuses on the expression and subcellular localisations of two long chain fatty acyl-CoA synthetase family members (ACSLs), ACSL3 and ACSL4, in HCC cells. ACSLs activate fatty acids through ATP-dependent Coenzyme A thioesterification to generate fatty acyl-CoAs that can enter a number of intracellular lipid metabolic pathways [14,15,16,17]. ACSL3 and ACSL4 are structurally homologous enzymes; they differ in their fatty acid substrate specificities, expression patterns
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
