Levels of acyl-Coenzyme A synthetase 5 in urothelial cells and corresponding neoplasias reflect cellular differentiation
Nadine T. Gaisa1*, Andrea Reinartz1*, Ursula Schneider1, Christina Klaus1, Axel Heidenreich2, Gerhard Jakse2, Elke Kaemmerer1,3, Barbara Mara Klinkhammer4, Ruth Knuechel1 and Nikolaus Gassler1
1Institute of Pathology, RWTH Aachen University, Aachen, Germany, 2Department of Urology, University Hospital Aachen, Aachen, Germany, 3Department of Paediatrics, University Hospital Aachen, Aachen, Germany and 4Department of Internal Medicine II, Nephrology and Clinical Immunology, University Hospital Aachen, Aachen, Germany
*NTG and AR share first authorship.
Offprint requests to: Prof. Dr. Nikolaus Gassler (M.A.), Institute of Pathology RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen. Germany. e-mail: firstname.lastname@example.org
Summary. Metabolic components like fatty acids and acyl-Coenzyme A (acyl-CoA) thioesters have been implicated in the pathogenesis of various tumours. The activation of fatty acids to acyl-CoAs is catalysed by long chain acyl-CoA synthetases (ACSLs), and impairment of ACSL expression levels has been associated with tumourigenesis and progression. Since ACSLs have never been investigated in bladder tissues, the study aims to characterize ACSL expression and acyl-CoA synthesis in normal and neoplastic bladder tissues, as well as cell lines. ACSL isoforms 1, 3, 4 and 5 and synthesis of acyl-CoAs were analysed using qRT-PCR, western blot analysis, immunohistochemistry and lipid mass spectrometry.
In normal urothelium, expression of ACSL1, 3, 4 and 5, with highest levels of ACSL isoform 5 was found. However, ACSL5 expression was reduced in corresponding neoplastic tissues and urothelial cell lines depending on the grade of cellular differentiation. Anti-ACSL5 immunostainings showed expression in normal urothelium and a gradual loss of ACSL5 protein via pre-invasive lesions to invasive carcinomas. High expression of ACSL5 correlated with increased α-galactosidase activity and positive Uroplakin III staining in tumours. In contrast, synthesis of acyl-CoAs was enhanced in neoplastic bladder tissues compared to normal urothelium, and reflected an increase with respect to cellular differentiation. These results confirm an expression of ACSLs, especially isoform 5, in human urothelium, prove enzymatic/lipidomic changes in bladder cancer tissues, and suggest an involvement of ACSL5 in cellular maturation and/or senescence with possible effects onto induction of tumour formation or progression. Further work may identify responsible pathway alterations, and attempting to re-balance the metabolic equilibrium of the urothelium may offer a further opportunity for tumour treatment and prevention. Histol Histopathol 28, 353-364 (2013)
Key words: ACSL, ACSL5, Bladder, Urothelium, Cancer