ECE2022 Poster Presentations Endocrine-Related Cancer (41 abstracts)
Elevated SGPL1 expression is associated with increased metabolic rate in cells and reduced survival in individuals with adrenocortical carcinoma
Jack Williams 1 , Chris Smith 1 , Charlotte Hall 1 , Zakaa Khaled 1 , Avinaash Maharaj 1 , Ruth Kwong 1 , James Pittaway 1 , Josefina Casas 2 , Laila Parvanta 3 , Tarek Abdel-Aziz 4 , Fausto Palazzo 5 , Teng-Teng Chung 4 , Leonardo Guasti 1 , Louise Metherell 1 & Rathi Prasad 1
1Queen Mary University Of London, Centre for Endocrinology, William Harvey Research Institute, London, United Kingdom; 2IQAC-CSIC, Research Unit on BioActive Molecules (RUBAM), Department of Biological Chemistry, Madrid, Spain; 3St Bartholomew’s Hospital, Department of Surgery, London, United Kingdom; 4University College London Hospitals NHS Foundation Trust, Department of Endocrinology, London, United Kingdom; 5Imperial College London, Department of Endocrine and Thyroid Surgery, London, United Kingdom
Introduction: Sphingosine-1-phosphate lyase (SGPL1) catalyses the final step in sphingolipid metabolism, irreversibly degrading the lipid signalling molecule sphingosine-1-phosphate (S1P). The relative abundance of S1P compared to its precursors sphingosine and ceramide finely tunes signal transduction for a wide range of cellular pathways including proliferation, apoptosis, migration and calcium handling. Loss-of-function mutations in SGPL1 cause a spectrum of disorders, including primary adrenal insufficiency (PAI). Adrenocortical carcinomas (ACCs) are invasive tumours arising in the adrenal cortex, and steroidogenic tumours are associated with worse prognostic outcomes. Given that loss of SGPL1 expression causes PAI, we hypothesised increased SGPL1 expression might increase steroidogenesis and therefore be linked to increase disease severity in ACC.
Methods: We analysed two ACC cohorts with survival data and corresponding RNA-seq/Microarray transcriptomic data, focusing on SGPL1 and other genes in the sphingolipid pathway. In vitro, we generated isogenic SGPL1-knockout and stable SGPL1-overexpressing H295R adrenocortical cells to better analyse the role of SGPL1 in cell signalling in ACCs. To investigate the effect of these perturbations on cell signalling and function we conducted assays for proliferation, migration, lipidomics, calcium signalling, apoptosis, autophagy, metabolism and gene/protein expression.
Results: We found increased SGPL1 expression correlated with reduced patient survival in two ACC cohorts, and a correlation in SGPL1 and Ki67 expression in a small cohort of ACC tissue samples. We also found a similar correlation in patient survival and sphingosine-1 kinase expression and the opposite correlation with patient survival and sphingosine-1-phosphatase expression. We noticed a marked increase in proliferation in SGPL1-overexpressing cells and a concordant decrease in proliferation in knockout cells. Similarly, overexpressing cells migrated faster while knockout cells were slower. SGPL1 overexpression significantly reduced levels of pro-apoptotic ceramides, although no reduction in apoptosis was observed. RNA-seq revealed a global increase in the expression of genes in the electron transport chain in overexpressing cells, correlating with increased aerobic respiration and glycolysis in these cells. Furthermore, the opposite phenotype was seen in cells lacking SGPL1. We subsequently found the increased proliferation is linked to metabolic substrate availability. We therefore propose that SGPL1-overexpressing ACC tumours reduce patient survival by increasing anabolism and energy availability for growth and invasion.
Conclusions: SGPL1 expression correlates with growth and migration rates in H295R cells, with knockout reducing steroidogenic capacity and overexpression increasing metabolism.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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