Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers: A novel therapeutic target

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Abstract

Inflammatory gastrointestinal (GI) diseases and malignancies are associated with growing morbidity and cancer-related mortality worldwide. GI tumor and inflammatory cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinase 1 (SphK1) and SphK2, that generate sphingosine-1-phosphate (S1P), a highly bioactive compound. Many inflammatory responses, including lymphocyte trafficking, are directed by circulatory S1P, present in high concentrations in both the plasma and the lymph of cancer patients. High fat and sugar diet, disbalanced intestinal flora, and obesity have recently been linked to activation of inflammation and SphK/S1P/S1P receptor (S1PR) signaling in various GI pathologies, including cancer. SphK1 overexpression and activation facilitate and enhance the development and progression of esophageal, gastric, and colon cancers. SphK/S1P axis, a mediator of inflammation in the tumor microenvironment, has recently been defined as a target for the treatment of GI disease states, including inflammatory bowel disease and colitis. Several SphK1 inhibitors and S1PR antagonists have been developed as novel anti-inflammatory and anticancer agents. In this review, we analyze the mechanisms of SphK/S1P signaling in GI tissues and critically appraise recent studies on the role of SphK/S1P/S1PR in inflammatory GI disorders and cancers. The potential role of SphK/S1PR inhibitors in the prevention and treatment of inflammation-mediated GI diseases, including GI cancer, is also evaluated.

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.

References (210)

  • H.G. Coleman et al.

    The epidemiology of esophageal adenocarcinoma

    Gastroenterology

    (2018)
  • R.D. Duan et al.

    Metabolism of sphingolipids in the gut and its relation to inflammation and cancer development

    Progress in Lipid Research

    (2009)
  • P.K. Dudeja et al.

    The role of sphingomyelin synthetase and sphingomyelinase in 1,2-dimethylhydrazine-induced lipid alterations of rat colonic plasma membranes

    Biochimica et Biophysica Acta

    (1986)
  • C.Q. Duong et al.

    Expression of the lysophospholipid receptor family and investigation of lysophospholipid-mediated responses in human macrophages

    Biochimica et Biophysica Acta

    (2004)
  • M.P. Espaillat et al.

    Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

    Advances in Biological Regulation

    (2017)
  • J. Ferlay et al.

    Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012

    European Journal of Cancer

    (2013)
  • T. Geng et al.

    SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes

    Journal of Lipid Research

    (2015)
  • A. Gómez-Muñoz et al.

    Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages

    Journal of Lipid Research

    (2004)
  • P. Grbčić et al.

    Dual sphingosine kinase inhibitor SKI-II enhances sensitivity to 5-fluorouracil in hepatocellular carcinoma cells via suppression of osteopontin and FAK/IGF-1R signalling

    Biochemical and Biophysical Research Communications

    (2017)
  • M. Gurgui et al.

    Dual action of sphingosine 1-phosphate in eliciting proinflammatory responses in primary cultured rat intestinal smooth muscle cells

    Cellular Signalling

    (2010)
  • Y. Hamada et al.

    Involvement of de novo ceramide synthesis in pro-inflammatory adipokine secretion and adipocyte-macrophage interaction

    The Journal of Nutritional Biochemistry

    (2014)
  • P.J. Harrison et al.

    Sphingolipid biosynthesis in man and microbes

    Natural Product Reports

    (2018)
  • T. Hla et al.

    Sphingolipid signaling in metabolic disorders

    Cell Metabolism

    (2012)
  • H. Ikeda et al.

    Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2

    Journal of Lipid Research

    (2009)
  • T. Ju et al.

    Targeting colorectal cancer cells by a novel sphingosine kinase 1 inhibitor PF-543

    Biochemical and Biophysical Research Communications

    (2016)
  • T. Karuppuchamy et al.

    Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease

    Mucosal Immunology

    (2017)
  • M. Kato et al.

    Sphingolipid composition in Bacteroides species

    Anaerobe

    (1995)
  • N. Kordjazy et al.

    Role of toll-like receptors in inflammatory bowel disease

    Pharmacological Research

    (2018)
  • H. Le Stunff et al.

    Recycling of sphingosine is regulated by the concerted actions of sphingosine-1-phosphate phosphohydrolase 1 and sphingosine kinase 2

    Journal of Biological Chemistry

    (2007)
  • H. Le Stunff et al.

    Sphingosine-1-phosphate and lipid phosphohydrolases

    Biochimica et Biophysica Acta

    (2002)
  • D.A. Lebman et al.

    Cross-talk at the crossroads of sphingosine-1-phosphate, growth factors, and cytokine signalling

    Journal of Lipid Research

    (2008)
  • J. Liang et al.

    Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer

    Cancer Cell

    (2013)
  • K.G. Lim et al.

    (R)-FTY720 methyl ether is a specific sphingosine kinase 2 inhibitor: Effect on sphingosine kinase 2 expression in HEK 293 cells and actin rearrangement and survival of MCF-7 breast cancer cells

    Cellular Signalling

    (2011)
  • H. Liu et al.

    SphK1 inhibitor SKI II inhibits the proliferation of human hepatoma HepG2 cells via the Wnt5A/β-catenin signaling pathway

    Life Sciences

    (2016)
  • L. Abdel Hadi et al.

    Sphingosine kinase 2 and ceramide transport as key targets of the natural flavonoid luteolin to induce apoptosis in colon cancer cells

    PLoS One

    (2015)
  • C.C. Abnet et al.

    Sphingolipids as biomarkers of fumonisin exposure and risk of esophageal squamous cell carcinoma in china

    Cancer Causes & Control

    (2001)
  • H. Al-Shamma et al.

    The selective sphingosine 1-phosphate receptor modulator etrasimod regulates lymphocyte trafficking and alleviates experimental colitis

    Journal of Pharmacology and Expimental Therapy

    (2019)
  • J.W. Antoon et al.

    Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance

    Oncology Reports

    (2012)
  • O. Arlt et al.

    Sphingosine-1-phosphate modulates dendritic cell function: focus on non-migratory effects in vitro and in vivo

    Cellular Physiology and Biochemistry

    (2014)
  • G. Aviello et al.

    ROS in gastrointestinal inflammation: Rescue Or Sabotage?

    British Journal of Pharmacology

    (2017)
  • D.A. Baker et al.

    Impact of sphingosine kinase 2 deficiency on the development of TNF-alpha-induced inflammatory arthritis

    Rheumatology International

    (2013)
  • V. Beljanski et al.

    Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts

    Cancer Biology & Therapy

    (2011)
  • J. Benktander et al.

    Helicobacter pylori SabA binding gangliosides of human stomach

    Virulence

    (2018)
  • N. Boku

    HER2-positive gastric cancer

    Gastric Cancer

    (2014)
  • F. Bourquin et al.

    PLP-dependent enzymes as entry and exit gates of sphingolipid metabolism

    Protein Science

    (2011)
  • E. Camerer et al.

    Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice

    The Journal of Clinical Investigation

    (2009)
  • L. Chen et al.

    Alphastatin downregulates vascular endothelial cells sphingosine kinase activity and suppresses tumor growth in nude mice bearing human gastric cancer xenografts

    World Journal of Gastroenterology

    (2006)
  • K. Chiba et al.

    Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus

    Cellular & Molecular Immunology

    (2006)
  • V. Chiurchiù et al.

    Bioactive lipids and chronic inflammation: Managing the fire within

    Frontiers in Immunology

    (2018)
  • A.A. Chumanevich et al.

    Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase

    Carcinogenesis

    (2010)
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