Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers: A novel therapeutic target
Introduction
As one of the most prominent public health problems, gastrointestinal (GI) and associated malignancies are characterized by high incidence and mortality rates. Denoting the magnitude and significance of this issue, colorectal (almost 215,000 deaths) and stomach cancers (107,000 deaths) were determined as the second and fourth most frequent causes of cancer-related death, respectively, in Europe in 2012 (Arnold et al., 2015; Ferlay et al., 2013). Closely associated to the growing incidence of obesity, GI cancers accounted for approximately 20% of all cancers in 2017 (Falzone, Salomone, & Libra, 2018; Ferlay et al., 2015). Besides an established link to diet and overweight, GI cancers can be initiated by a complex interplay between host genetic and environmental factors, lifestyle and habits, diet, intestinal bacterial components, and inflammation (Espaillat, Kew, & Obeid, 2017; Falzone et al., 2018). Considering the constant exposure to chemical and bacterial loading, the digestive system is a unique structure that developed complex mechanisms of resistance and tolerance to continuous pro-inflammatory stimuli (Linnebacher, Maletzki, Klier, & Klar, 2012). Substantial breaches in the GI immune and barrier function have been linked to malignant transformation (Argollo, Fiorino, Hindryckx, Peyrin-Biroulet, & Danese, 2017). Activation of various pro-inflammatory pathways, including production of reactive oxygen species [Aviello & Knaus, 2017], eicosanoids [Wallace, 2019], and activation of Toll-like receptor signaling [Kordjazy et al., 2018], were linked to GI inflammation and cancer. The pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) signaling pathway is the most studied mechanism that mediates GI inflammation (Argollo et al., 2017). Specific targeting of TNF-α effects and its down-stream effectors is considered promising for future drug discovery and development. Sphingolipid signaling was identified as one of the mediators of pro-inflammatory GI events, and, specifically, TNF-α related signaling (Geng et al., 2015; Hait & Maiti, 2017). Besides inflammatory pathologies, several recent investigations have also demonstrated the important pathophysiological role of sphingolipids in GI malignancies (Hait & Maiti, 2017;Huang et al., 2016 ; Pan et al., 2011).
Among the large number of sphingolipid family members, sphingosine-1-phosphate (S1P) was shown to influence inflammatory responses and carcinogenesis in different tissues (Sukocheva, 2018), including the development and progression of GI malignancies (Huang et al., 2016; Pan et al., 2011). Enhanced S1P concentrations, detected at the sites of inflammation, intensify inflammatory signaling, engagement of immune cells, and further release of other pro-inflammatory agents (Hait & Maiti, 2017; Peyrin-Biroulet, Christopher, Behan, & Lassen, 2017). S1P is a product of sphingosine kinases (SphK1 and SphK2) that utilize sphingosine during the degradation of plasma membrane glycosphingolipids and sphingomyelin (Duan & Nilsson, 2009; Sukocheva, 2018). The major enzymes that are responsible for sphingomyelin degradation in the intestinal lumen and mucosa are alkaline sphingomyelinase and neutral ceramidase (N-ceramidase) (Duan & Nilsson, 2009) (Fig. 1). While sphingomyelin was shown to inhibit phospholipase 2 (PLA2), one of the major effectors of inflammatory cascade, and thus, prevent activation of inflammation, the downstream products of sphingomyelin degradation, ceramide-1-phosphate (C1P) and S1P were reported to activate PLA2, induce expression of cyclooxygenase 2 (COX-2), and promote inflammation (Gurgui, Broere, Kalff, & van Echten-Deckert, 2010; Pettus et al., 2005). Considering the availability of growing amount of research data and recent clinical success in application of S1P receptor inhibitor FTY720/fingolimod against several pro-inflammatory conditions, including multiple sclerosis, this review will describe the role of S1P axis in gastrointestinal inflammation and cancers.
S1P is a structural, metabolic, and bioactive lipid involved in the regulation of various physiological responses, including cell growth, transformation, migration, and cell death. Intracellular S1P can be dephosphorylated back to sphingosine by phosphatases or irreversibly degraded by S1P lyase to hexadecenal and ethanolamine phosphate (Fig. 1) (Bourquin, Capitani, & Grütter, 2011; Olivera, Allende, & Proia, 2013). S1P was detected in circulation associated with albumin or high-density lipoprotein (HDL). Albumin-bound S1P that is released from liver and skeletal muscles is destined to degrade in the pulmonary and gastrointestinal circulation (Książek, Baranowska, Chabowski, & Baranowski, 2018). Liver is also an important source of HDL-bound S1P in circulation (Książek et al., 2018). When present in the extracellular space, S1P can bind and activate specific S1P receptors (S1PR) (S1Pn, n = 1 to 5) differentially expressed in various tissues, including all GI and associated organs (Kawakita et al., 2017; Matula et al., 2015; Wang et al., 2014). Notably, the expression levels of S1PRs were shown to fluctuate in different directions (depending on the type of S1PR) during malignant transformation and inflammation (Kawakita et al., 2017; Peyrin-Biroulet et al., 2017). Binding of S1P to S1PRs results in internalization of the receptors and their degradation or recycling associated with transient changes in S1PRs expression levels (Sukocheva, Wadham, & Xia, 2013). As a down-stream signal transducer, the SphK/S1PR axis mediates the effects of many pro-inflammatory, growth stimulatory, and pro-angiogenic factors during tumorigenesis (Sukocheva, 2018). Distinct effects of sphingolipids, and specifically S1P signaling axis, in regulation of innate and adaptive immunity, immunosurveillance, immune cell trafficking and differentiation, release of cytokines, and endothelial barrier integrity are mediated by S1P binding to S1PRn (n = 1–5) (Hla & Dannenberg, 2012; Maceyka & Spiegel, 2014). Furthermore, the focus on S1PRs in GI inflammation is defined by ubiquitous expression of these receptors in nearly all GI tissues and possibility to amend inflammation-related pathologies and GI cancers via modification of S1P signaling mechanisms. In this review, we discuss recent advances in the involvement of SphK/S1P/S1PR signaling in the regulation of homeostasis and inflammation-linked responses in normal and malignant GI cells and tissues. Furthermore, we specifically evaluate the significance of the suggested mechanisms of sphingolipid signaling in esophageal, gastric, and colon malignancies and specific inflammatory pathologies. The network crosstalk with other GI regulatory agents including hormones, cytokines, and growth factors is also noted. Future perspectives and potential drug targets are also discussed.
Section snippets
Sphingolipids as regulators and mediators of inflammation: An introductory overview
The SphK/S1P axis is activated during the initiation and progression of immune responses (Hait & Maiti, 2017; Niwa et al., 2000; Rivera, Proia, & Olivera, 2008; Xia et al., 1998). A range of pro-inflammatory cytokines and coagulation-related substances stimulates sphingolipid metabolism and activates the SphK/S1P signaling network (Proia & Hla, 2015; Rivera et al., 2008). S1PRs are expressed in various immune cell subtypes, including monocytes/macrophages, neutrophils (during inflammation),
Role of Sphingolipid signaling in development and progression of GI inflammation-related pathologies including inflammatory bowel disease
Inflammatory bowel disease (IBD) is a severe lower intestine inflammatory disorder that incorporates a group of illnesses, including Crohn's disease and ulcerative colitis (UC). IBD is marked by chronic, progressive and disabling conditions that negatively impact quality of life requiring lifelong medical treatment (Baumgart & Sandborn, 2007). Complex genetic and acquired innate/adaptive immune system characteristics, introduced environmental components (i.e., external pathogenic microorganisms
Esophageal cancers and associated pathologies
Esophageal cancer is one of the most frequent neoplasms responsible for cancer-related deaths worldwide. Despite some modest progress in treatment, this type of cancer remains a clinically challenging disease that demands a multidisciplinary approach, but unfortunately fails to extend survival time (Uemura & Kondo, 2016). According to histological characteristics, the majority of esophageal cancers are represented by squamous cell carcinomas and adenocarcinomas. Incidence of both types is
Inhibitors of SphK/S1PR signaling for prevention and treatment of inflammation-mediated GI disorder and cancer
SphK/S1PR signaling axis was recognized as an important target for therapeutic interventions. Several SphK/S1PR inhibitors were successfully tested in clinical trials (Di Pardo & Maglione, 2018; French et al., 2003; Geng et al., 2015; Stepanovska & Huwiler, 2019). One of the most promising agents, FTY720 [2-amino-2-(2-(4octylphenyl)ethyl)propane-1,3-diol; also known as fingolimod] demonstrated favorable anti-proliferative effects in multiple cancer cells (Di Pardo & Maglione, 2018; Stepanovska
Conclusion and future perspectives
Pharmacological targeting of the inflammatory tumor microenvironment is considered as highly beneficial because, firstly, immune cells did not demonstrate similar mechanisms of drug resistance as cancer cells, and, secondly, anti-inflammatory therapies indicated promising data for cancer prevention at the earlier stages. Accordingly, inflammation-related signaling pathways attract growing interest. Acute and chronic inflammatory processes are tightly intervened and mediated by sphingolipid
Declaration of Competing Interest
The authors declare that there are no conflicts of interest. The work has been approved by all authors.
Acknowledgements
Vadim V. Tarasov, Vladimir N. Chubarev, and Gjumrakch Aliev have been supported by the Russian Academic Excellence Project "5-100” granted at the Sechenov University, Moscow, Russian Federation. Sergey G. Klochkov, Margarita E. Neganova, and Gjumrakch Aliev are supported by the Russian Federation for Basic Research funding under scientific project No. 18-33-20209. Gjumrakch Aliev’s work is also supported by the GALLY International Research Institute, San Antonio, TX, USA.
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