Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
TP53 is required for BECN1- and ATG5-dependent cell death induced by sphingosine kinase 1 inhibition.
Santiago Lima,Kazuaki Takabe,Jason Newton,Kumar Saurabh,Megan M. Young,Andréia Machado Leopoldino,Nitai C. Hait,Jane L. Roberts,Hong Gang Wang,Paul Dent,Sheldon Milstien,Laurence Booth,Sarah Spiegel +12 more
TL;DR: TP53 plays an important role in vacuole-associated cell death induced by SPHK1 inhibition in cancer cells, and downregulation of the key regulators of autophagic flux, BECN1 and ATG5, dramatically decreased the cytotoxicity of SK1-I only in cells with TP53 expression.
Journal ArticleDOI
Sphingosine 1-phosphate as a link between blood coagulation and inflammation.
TL;DR: It is concluded that S1P might represent an until now underestimated lipid mediator of inflammatory reactions following activation of the clotting system and, in this context, also involved in the development and progression of atherosclerosis.
Journal ArticleDOI
Sphingosine-1-phosphate receptor 1 mediates elevated IL-6 signaling to promote chronic inflammation and multitissue damage in sickle cell disease.
Shushan Zhao,Morayo G. Adebiyi,Yujin Zhang,Jacob Couturier,Xuegong Fan,Hongqi Zhang,Rodney E. Kellems,Dorothy E. Lewis,Yang Xia +8 more
TL;DR: It is revealed that elevated S1P, coupled with macrophage S1PR1 reciprocally inducing IL‐6 expression, is a key signaling network functioning as a malicious, positive, feed‐forward loop to sustain inflammation and promote tissue damage in SCD.
Journal ArticleDOI
Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity
Elizabeth S. Childress,Yugesh Kharel,Anne M. Brown,David R. Bevan,Kevin R. Lynch,Webster L. Santos +5 more
TL;DR: In vivo administration of 20dd validated that inhibition of SphK2 increases blood S1P levels, and the design, synthesis, and biological evaluation of aminothiazole-based guanidine inhibitors of sphingosine 1-phosphate were validated.
Journal ArticleDOI
Angiocrine Sphingosine-1-Phosphate Activation of S1PR2-YAP Signaling Axis in Alveolar Type II Cells Is Essential for Lung Repair.
Qian Chen,Jalees Rehman,Manwai Chan,Panfeng Fu,Steven M. Dudek,Viswanathan Natarajan,Asrar B. Malik,Yuru Liu +7 more
TL;DR: Angiocrine S1P released after injury acts via the S1PR2-YAP signaling axis on AT2 cells to promote AT2 to AT1 differentiation required for alveolar repair, demonstrating the role of the LMVEC-derived bioactive lipid sphingosine-1-phosphate (S1P).
References
More filters
Journal ArticleDOI
STATs in cancer inflammation and immunity: a leading role for STAT3
TL;DR: Signal transducer and activator of transcription proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer, and STAT3 is a promising target to redirect inflammation for cancer therapy.
Journal ArticleDOI
Principles of bioactive lipid signalling: lessons from sphingolipids
TL;DR: An understanding of the complex pathways of sphingolipid metabolism and the mechanisms that regulate lipid generation and lipid action is required to understand the mechanisms of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking.
Journal ArticleDOI
The many roles of histone deacetylases in development and physiology: Implications for disease and therapy
TL;DR: In this article, the expression of many HDAC isoforms in eukaryotic cells raises questions about their possible specificity or redundancy, and whether they control global or specific programs of gene expression.
Journal Article
Heart-lung transplantation.
TL;DR: A broad overview of the various grounds upon which this difference is likely based and discuss recent advances in each area: 1) criteria for the selection of candidates and donors, 2) methods for ex-vivo preservation of donor organs, 3) technical execution of the operative procedure, and 4) prevention of postoperative infection as discussed by the authors.
Journal ArticleDOI
Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase
Liming Sun,Huayi Wang,Zhigao Wang,Sudan He,She Chen,Daohong Liao,Lai Wang,Jiacong Yan,Weilong Liu,Xiaoguang Lei,Xiaodong Wang +10 more
TL;DR: The identification of a small molecule called necrosulfonamide that specifically blocks necrosis downstream of RIP3 activation is reported, which implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3.