The role of sphingosine 1-phosphate in inflammation and cancer

Abstract

This version is available at https://strathprints.strath.ac.uk/49243/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. The lipid sphingosine 1-phosphate (S1P) is a key regulator of cell growth, survival, invasion, lymphocyte trafficking, vascular integrity and cytokine production, and plays a central role in inflammatory disease and cancer. S1P is formed by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SK1 and SK2) that differ in their biochemical properties, sub-cellular localization, and function (Pyne and Pyne, 2011). S1P is cleaved by S1P lyase to produce trans-2-hexadecenal and phosphoethanolamine. S1P can also be dephosphorylated by S1P phosphatases to recycle into sphingolipids (Pyne and Pyne, 2011). S1P is an agonist of S1P-specific G-protein coupled receptors, termed S1P 1-5 , and also binds to intracellular protein targets, such as histone deacetylase 1 and 2 (HDAC1/2, which regulate gene expression) (for review see

Sphingosine-1-phosphate and estrogen signaling in breast cancer

“…Moreover, expression of SphK1 has been shown to correlate with poor prognosis in breast cancer patients (Pyne et al, 2014;Ruckhaberle et al, 2008). Fig.…”

“…Our initial demonstration that overexpression of SphK1 in human breast cancer cells promoted tumorigenesis and neovascularization when implanted in nude mice (Nava et al, 2002) was followed by numerous reports confirming the importance of SphK1 and formation of S1P as anti-apoptotic and growth-promoting factors in breast cancer (Carroll et al, 2015;Newton et al, 2015;Pyne et al, 2014;Sukocheva and Wadham, 2014;Truman et al, 2014). Moreover, expression of SphK1 has been shown to correlate with poor prognosis in breast cancer patients (Pyne et al, 2014;Ruckhaberle et al, 2008).…”

“…SphK1 expression and activity were shown to be elevated in acquired-tamoxifen resistant ERa-positive MCF7 cells, and SphK1 inhibition or downregulation restored the anti-proliferative and pro-apoptotic effects of tamoxifen (Sukocheva et al, 2009;Watson et al, 2010). In a cohort of 304 ERa-positive breast cancer patients, SphK1 expression correlated with tamoxifen resistance (Pyne et al, 2012). Moreover, high SphK1 and ERK1/2 expression in tumors of ERapositive breast cancer patients, high S1PR1, but not S1PR2, expression, and higher expression of S1PR1/3 and ERK1/2 were all found to be associated with shorter time to recurrence on tamoxifen (Watson et al, 2010).…”

“…Physiological responses regulated by S1P depend on the spectrum of ubiquitously but differentially expressed S1PRs and the variety of G proteins they are coupled to. Thus, many signaling pathways downstream of S1PRs that have been linked to cancer progression have been shown to be activated depending on the cell type, including MAPKs, phospholipase C, adenylate cyclase, and Rac/PI3K/Akt, to name a few (Pyne et al, 2014;Takabe et al, 2008). Moreover, various types of cancer cells differentially express different sets of S1PRs, thus providing S1P with the ability to regulate numerous cellular processes important for breast cancer, including growth, survival, migration, invasion, inflammation, angiogenesis, and lymphangiogenesis (Nagahashi et al, 2014).…”

Regulation of de novo sphingolipid biosynthesis by the ORMDL proteins and sphingosine kinase-1

“…Sphingolipids have long been considered important, but enigmatic, second messengers and components of cellular membranes with critical roles in health and disease (reviewed in Hannun and Obeid 2002;Huwiler et al, 2000;Nagahashi et al, 2014;Pyne et al, 2014). The regulation of levels of these lipids is complex, with multiple enzymatic pathways mediating the reversible interconversion of virtually every sphingolipid species (Fig.…”