Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond
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TLDR
The ways in which S1P might be therapeutically targeted are discussed — for example, via the development of chemical inhibitors that target the generation, transport and degradation of S 1P and via thedevelopment of specific S1p receptor agonists.Abstract:
The bioactive lipid sphingosine-1-phosphate (S1P) is involved in multiple cellular signalling systems and has a pivotal role in the control of immune cell trafficking. As such, S1P has been implicated in disorders such as cancer and inflammatory diseases. This Review discusses the ways in which S1P might be therapeutically targeted — for example, via the development of chemical inhibitors that target the generation, transport and degradation of S1P and via the development of specific S1P receptor agonists. We also highlight recent conflicting results observed in preclinical studies targeting S1P and discuss ongoing clinical trials in this field.read more
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References
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Journal ArticleDOI
An update on sphingosine-1-phosphate and other sphingolipid mediators.
Henrik Fyrst,Julie D. Saba +1 more
TL;DR: Preclinical and clinical investigations using pharmacological agents that target sphingosine-1-phosphate, its receptors and the enzymes required for its biosynthesis and degradation demonstrate the promise and potential risks of modulating sphingOSine- 1- phosphate signaling in treatment strategies for autoimmunity, cancer, cardiovascular disease and other pathological conditions.
Journal ArticleDOI
Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration
Graham M. Strub,M. Paillard,Jie Liang,Ludovic Gomez,Jeremy C. Allegood,Nitai C. Hait,Michael Maceyka,Megan M. Price,Qun Chen,David Simpson,Tomasz Kordula,Sheldon Milstien,Edward J. Lesnefsky,Sarah Spiegel +13 more
TL;DR: It is demonstrated that S1P, produced in the mitochondria mainly by sphin‐gosine kinase 2 (SphK2), binds with high affinity and specificity to prohibitin 2 (PHB2), a highly conserved protein that regulates mitochondrial assembly and function.
Journal ArticleDOI
T-bet–dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow
Craig N. Jenne,Anselm Enders,Richard Rivera,Susan R. Watson,Alexander J. Bankovich,João Pereira,Ying Xu,Carla M. Roots,Joshua N. Beilke,Arnob Banerjee,Steven L. Reiner,Sara A. Miller,Amy S. Weinmann,Christopher C. Goodnow,Lewis L. Lanier,Jason G. Cyster,Jerold Chun +16 more
TL;DR: Findings identify S1P5 as a T-bet–induced gene that is required for NK cell egress from LNs and BM, and suggests a role for S1p in BM egress.
Journal ArticleDOI
The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice
Shigetomo Fukuhara,Szandor Simmons,Shunsuke Kawamura,Asuka Inoue,Yasuko Orba,Takeshi Tokudome,Yuji Sunden,Yuji Arai,Kazumasa Moriwaki,Junji Ishida,Akiyoshi Uemura,Hiroshi Kiyonari,Takaya Abe,Akiyoshi Fukamizu,Masanori Hirashima,Hirofumi Sawa,Junken Aoki,Masaru Ishii,Naoki Mochizuki +18 more
TL;DR: It is shown that in mice, the S1P transporter spinster homolog 2 (Spns2) is responsible for the egress of mature T cells and immature B cells from the thymus and bone marrow, respectively, and that Spns2 functions in ECs to establish the S 1P gradient required for T and B cells to egress from their respective primary lymphoid organs.
Journal ArticleDOI
Pharmacology and Antitumor Activity of ABC294640, a Selective Inhibitor of Sphingosine Kinase-2
Kevin J. French,Yan Zhuang,Lynn W. Maines,Peng Gao,Wenxue Wang,Vladimir Beljanski,John J. Upson,Cecelia L. Green,Staci N. Keller,Charles D. Smith +9 more
TL;DR: Oral administration of ABC294640 to mice bearing mammary adenocarcinoma xenografts results in dose-dependent antitumor activity associated with depletion of S1P levels in the tumors and progressive tumor cell apoptosis, and this newly developed SK2 inhibitor provides an orally available drug candidate for the treatment of cancer and other diseases.