TY - JOUR
T1 - Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers
T2 - A novel therapeutic target
AU - Sukocheva, Olga A.
AU - Furuya, Hideki
AU - Ng, Mei Li
AU - Friedemann, Markus
AU - Menschikowski, Mario
AU - Tarasov, Vadim V.
AU - Chubarev, Vladimir N.
AU - Klochkov, Sergey G.
AU - Neganova, Margarita E.
AU - Mangoni, Arduino A.
AU - Aliev, Gjumrakch
AU - Bishayee, Anupam
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
KW - Colitis
KW - Colon cancer
KW - Esophageal cancer
KW - Fingolimod
KW - Gastric cancer
KW - Inflammatory bowel disease
KW - Microbiome
KW - Sphingosine kinase
KW - Sphingosine-1-phosphate
KW - Sphingosine-1-phosphate receptor
UR - http://www.scopus.com/inward/record.url?scp=85077395910&partnerID=8YFLogxK
U2 - 10.1016/j.pharmthera.2019.107464
DO - 10.1016/j.pharmthera.2019.107464
M3 - Review article
C2 - 31863815
AN - SCOPUS:85077395910
VL - 207
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
SN - 0163-7258
M1 - 107464
ER -