The atypical sphingosine 1‐phosphate variant, d16:1 S1P, mediates CTGF induction via S1P2 activation in renal cell carcinoma. (3rd April 2022)

• Record Type: Journal Article
• Authors: Glueck, Melanie; Koch, Alexander; Brunkhorst, Robert; Ferreiros Bouzas, Nerea; Trautmann, Sandra; Schaefer, Liliana; Pfeilschifter, Waltraud; Pfeilschifter, Josef; Vutukuri, Rajkumar
• Is Part Of: FEBS journal. Volume 289:Number 18(2022)
• Page Start: 5670
• Page End: 5681
• Publication Date: 2022-04-03
• Subjects: A498 cells -- CTGF -- RCC -- S1P receptors -- sphingosine 1‐phosphate homologues; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.16446
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Sphingosine 1‐phosphate (S1P) is a lipid mediator with numerous biological functions. The term 'S1P' mainly refers to the sphingolipid molecule with a long‐chain sphingoid base of 18 carbon atoms, d18:1 S1P. The enzyme serine palmitoyltransferase catalyses the first step of the sphingolipid de novo synthesis using palmitoyl‐CoA as the main substrate. After further reaction steps, d18:1 S1P is generated. However, also stearyl‐CoA or myristoyl‐CoA can be utilised by the serine palmitoyltransferase, which at the end of the S1P synthesis pathway, results in the production of d20:1 S1P and d16:1 S1P respectively. We measured these S1P homologues in mice and renal tissue of patients suffering from renal cell carcinoma (RCC). Our experiments highlight the relevance of d16:1 S1P for the induction of connective tissue growth factor (CTGF) in the human renal clear cell carcinoma cell line A498 and human RCC tissue. We show that d16:1 S1P versus d18:1 and d20:1 S1P leads to the highest CTGF induction in A498 cells via S1P2 signalling and that both d16:1 S1P and CTGF levels are elevated in RCC compared to adjacent healthy tissue. Our data indicate that d16:1 S1P modulates conventional S1P signalling by acting as a more potent agonist at the S1P2 receptor than d18:1 S1P. We suggest that elevated plasma levels of d16:1 S1P might play a pro‐carcinogenic role in the development of RCC via CTGF induction. Abstract : In renal cell carcinoma (RCC), the levels of d18:1 S1P and d16:1 S1P were elevated in comparison to the corresponding controls. Using the RCC cell line A498, we identified d16:1 S1P and d18:1 S1P to enhance connective tissue growth factor (CTGF) expression via the S1P2 receptor. CTGF was reported to play a role in carcinogenic processes such as metastasis. Upon blocking the S1P2 receptor with JTE‐013, the levels of CTGF were downregulated. Targeting the S1P2 receptor‐mediated CTGF expression could improve the outcome of RCC.