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https://www.readbyqxmd.com/read/28415564/mammalian-sphingosine-kinase-sphk-isoenzymes-and-isoform-expression-challenges-for-sphk-as-an-oncotarget
#1
REVIEW
Diana Hatoum, Nahal Haddadi, Yiguang Lin, Najah T Nassif, Eileen M McGowan
The various sphingosine kinase (SphK) isoenzymes (isozymes) and isoforms, key players in normal cellular physiology, are strongly implicated in cancer and other diseases. Mutations in SphKs, that may justify abnormal physiological function, have not been recorded. Nonetheless, there is a large and growing body of evidence demonstrating the contribution of gain or loss of function and the imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes and inflammatory diseases...
March 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28406646/transforming-sphingosine-kinase-1-inhibitors-into-dual-and-sphingosine-kinase-2-selective-inhibitors-design-synthesis-and-in-vivo-activity
#2
Elizabeth S Childress, Yugesh Kharel, Anne M Brown, David R Bevan, Kevin R Lynch, Webster L Santos
Sphingosine 1-phosphate (S1P) is a pleotropic signaling molecule that interacts with its five G-protein coupled receptors S1P1-5 to regulate cell growth and survival and has been implicated in a variety of diseases including cancer and sickle cell disease. As the key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmaceutical inhibition. In this report, we describe the design, synthesis, and biological evaluation of aminothiazole-based guanidine inhibitors of SphK...
April 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28377281/novel-sphingosine-kinase-1-inhibitor-lcl351-reduces-immune-responses-in-murine-dss-induced-colitis
#3
Michael J Pulkoski-Gross, Joachim D Uys, K Alexa Orr-Gandy, Nicolas Coant, Agnieszka B Bialkowska, Zdzislaw M Szulc, Aiping Bai, Alicja Bielawska, Danyelle M Townsend, Yusuf A Hannun, Lina M Obeid, Ashley J Snider
Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid metabolite which has been implicated in many diseases including cancer and inflammatory diseases. Recently, sphingosine kinase 1 (SK1), one of the isozymes which generates S1P, has been implicated in the development and progression of inflammatory bowel disease (IBD). Based on our previous work, we set out to determine the efficacy of a novel SK1 selective inhibitor, LCL351, in a murine model of IBD. LCL351 selectively inhibits SK1 both in vitro and in cells...
April 2, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28364399/sphingosine-1-phosphate-sphingosine-kinase-1-dependent-lymph-node-metastasis-in-esophageal-squamous-cell-carcinoma
#4
Yuta Kawakita, Satoru Motoyama, Yusuke Sato, Souichi Koyota, Akiyuki Wakita, Jiajia Liu, Hajime Saito, Yoshihiro Minamiya
PURPOSE: To establish whether Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SphK1) contribute to lymph node metastasis in esophageal squamous cell carcinoma. METHODS: Immunohistochemical analysis of SphK1 expression was performed using a tissue microarray containing 177 thoracic squamous cell esophageal cancer specimens resected at surgery, to investigate the association between intratumoral SphK1 expression and lymph node metastasis. Serum S1P levels and intratumoral SphK1 mRNA and protein expression were also evaluated in mice with vs...
March 31, 2017: Surgery Today
https://www.readbyqxmd.com/read/28362332/sphingosine-1-phosphate-metabolism-and-its-role-in-the-development-of-inflammatory-bowel-disease
#5
REVIEW
Tomasz Wollny, Marzena Wątek, Bonita Durnaś, Katarzyna Niemirowicz, Ewelina Piktel, Małgorzata Żendzian-Piotrowska, Stanisław Góźdź, Robert Bucki
Beyond their role as structural molecules, sphingolipids are involved in many important cellular processes including cell proliferation, apoptosis, inflammation, and migration. Altered sphingolipid metabolism is observed in many pathological conditions including gastrointestinal diseases. Inflammatory bowel disease (IBD) represents a state of complex, unpredictable, and destructive inflammation of unknown origin within the gastrointestinal tract. The mechanisms explaining the pathophysiology of IBD involve signal transduction pathways regulating gastro-intestinal system's immunity...
March 31, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28351953/sphingosine-1-phosphate-signaling-through-its-receptor-s1p5-promotes-chromosome-segregation-and-mitotic-progression
#6
Guillaume Andrieu, Adeline Ledoux, Sophie Branka, Magalie Bocquet, Julia Gilhodes, Thierry Walzer, Kousuke Kasahara, Masaki Inagaki, Roger A Sabbadini, Olivier Cuvillier, Anastassia Hatzoglou
Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein-coupled receptors (S1P1-5) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis. SphK1 depletion in HeLa cells caused prometaphase arrest, whereas its overexpression or activation accelerated mitosis...
March 28, 2017: Science Signaling
https://www.readbyqxmd.com/read/28322796/modulation-of-the-sphingolipid-rheostat-is-involved-in-paclitaxel-resistance-of-the-human-prostate-cancer-cell-line-pc3-pr
#7
Yuka Aoyama, Sayaka Sobue, Naoki Mizutani, Chisato Inoue, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Mamoru Kyogashima, Motoshi Suzuki, Yoshinoti Nozawa, Takashi Murate
Taxoids are anti-cancer drugs frequently used to treat solid tumors, but they are sometimes ineffective and tumors may become resistant to their action. Here, we examined the involvement of sphingolipid metabolic enzymes in paclitaxel (PTX) resistance using a human prostate cancer cell line, PC3, and its PTX-resistant subline, PC3-PR. PTX (20 nM) suppressed cell proliferation and increased various ceramide species in PC3, but not PC3-PR, cells. PC3-PR contained higher S1P levels than did PC3, regardless of PTX treatment...
March 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28302566/mechanisms-of-sphingosine-1-phosphate-receptor-signalling-in-cancer
#8
REVIEW
Sathya Narayanan Patmanathan, Wei Wang, Lee Fah Yap, Deron R Herr, Ian C Paterson
S1P is a small bioactive lipid which exerts its effects following binding to a family of five G protein-coupled receptors, known as S1P1-5. Following receptor activation, multiple signalling cascades are activated, allowing S1P to regulate a range of cellular processes, such as proliferation, apoptosis, migration and angiogenesis. There is strong evidence implicating the involvement of S1P receptors (S1PRs) in cancer progression and the oncogenic effects of S1P can result from alterations in the expression of one or more of the S1PRs and/or the enzymes that regulate the levels of S1P...
March 14, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28279838/modulation-of-sphingosine-1-phosphate-in-inflammatory-bowel-disease
#9
REVIEW
Laurent Peyrin-Biroulet, Ronald Christopher, Dominic Behan, Cheryl Lassen
Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, involve an inappropriate immune reaction in the digestive tract, causing a variety of disabling symptoms. The advent of monoclonal antibodies (anti-tumor necrosis factor, anti-integrin, anti-interleukin -23) has revolutionized IBD management. Nevertheless, these agents, with potential for immunogenicity, are associated with high rates of response loss and disease relapse over time. They are also associated with high production costs...
March 7, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/28270699/fty720-attenuates-angiotensin-ii-induced-podocyte-damage-via-inhibiting-inflammatory-cytokines
#10
Ke Su, Ping Zeng, Wei Liang, Zhengyu Luo, Yiman Wang, Xifeng Lv, Qi Han, Miao Yan, Cheng Chen
FTY720, a new chemical substance derived from the ascomycete Isaria sinclairii, is used for treating multiple sclerosis, renal cancer, and asthma. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite and exists in red blood cells. FTY720 is a synthetic S1P analog which can block S1P evoking physiological effects. Recently studies show that S1P was participating in activated inflammation cells induced renal injury. The objective of this study was to assess the protective effect of FTY720 on kidney damage and the potential mechanism of FTY720 which alleviate podocyte injury in chronic kidney disease...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28270071/inhibitory-effects-of-novel-sphk2-inhibitors-on-migration-of-cancer-cells
#11
Deokho Jung, Junghyun Jung, Euiyeon Lee, Chang Soo Mok, Hyunjin Jeon, Chang Seo Park, Wonhee Jang, Youngeun Kwon
Cell migration is an essential process for survival and differentiation of mammalian cells. Numerous diseases are induced or influenced by inappropriate regulation of cell migration, which plays a key role in cancer cell metastasis. In fact, very few anti-metastasis drugs are available on the market. SphKs are enzymes that convert sphingosine to sphingosine-1- phosphate (S1P) and are known to control various cellular functions, including migration of cells. Among two human isozymes of SphK2, SphK2 is known to promote apoptosis, suppresses cell growth, and controls cell migration; in addition, the specific ablation of SphK2 activity was reported to inhibit cancer cell metastasis...
February 13, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28248965/pancreas-lineage-allocation-and-specification-are-regulated-by-sphingosine-1-phosphate-signalling
#12
Ioannis Serafimidis, Eva Rodriguez-Aznar, Mathias Lesche, Kazuaki Yoshioka, Yoh Takuwa, Andreas Dahl, Duojia Pan, Anthony Gavalas
During development, progenitor expansion, lineage allocation, and implementation of differentiation programs need to be tightly coordinated so that different cell types are generated in the correct numbers for appropriate tissue size and function. Pancreatic dysfunction results in some of the most debilitating and fatal diseases, including pancreatic cancer and diabetes. Several transcription factors regulating pancreas lineage specification have been identified, and Notch signalling has been implicated in lineage allocation, but it remains unclear how these processes are coordinated...
March 2017: PLoS Biology
https://www.readbyqxmd.com/read/28241498/sphingosine-1-phosphate-receptor-1-signaling-in-mammalian-cells
#13
REVIEW
Nigel J Pyne, Susan Pyne
The bioactive lipid, sphingosine 1-phosphate (S1P) binds to a family of G protein-coupled receptors, termed S1P₁-S1P₅. These receptors function in, for example, the cardiovascular system to regulate vascular barrier integrity and tone, the nervous system to regulate neuronal differentiation, myelination and oligodendrocyte/glial cell survival and the immune system to regulate T- and B-cell subsets and trafficking. S1P receptors also participate in the pathophysiology of autoimmunity, inflammatory disease, cancer, neurodegeneration and others...
February 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28240350/oncogenic-s1p-signalling-in-ebv-associated-nasopharyngeal-carcinoma-activates-akt-and-promotes-cell-migration-through-s1p-receptor-3
#14
Hui Min Lee, Kwok-Wai Lo, Wenbin Wei, Sai Wah Tsao, Grace Tin Yun Chung, Maha Hafez Ibrahim, Christopher W Dawson, Paul G Murray, Ian C Paterson, Lee Fah Yap
Undifferentiated nasopharyngeal carcinoma (NPC) is a cancer with high metastatic potential that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the functional contribution of sphingosine-1-phosphate (S1P) signalling to the pathogenesis of NPC. We show that EBV infection or ectopic expression of the EBV-encoded latent genes (EBNA1, LMP1, and LMP2A) can up-regulate sphingosine kinase 1 (SPHK1), the key enzyme that produces S1P, in NPC cell lines. Exogenous addition of S1P promotes the migration of NPC cells through the activation of AKT; shRNA knockdown of SPHK1 resulted in a reduction in the levels of activated AKT and inhibition of cell migration...
February 27, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28231433/discovery-of-a-potent-and-selective-sphingosine-kinase-1-inhibitor-through-the-molecular-combination-of-chemotype-distinct-screening-hits
#15
Mark E Schnute, Matthew D McReynolds, Jeffrey Carroll, Jill Chrencik, Maureen K Highkin, Kaliapan Iyanar, Gina Jerome, John W Rains, Matthew Saabye, Jeffrey A Scholten, Matthew Yates, Marek M Nagiec
Sphingosine kinase (SphK) is the major source of the lipid mediator and G protein-coupled receptor agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival, and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme-based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound 22a (PF-543) with 2 orders of magnitude improved potency...
March 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28224210/tumor-specific-regulatory-t-cells-in-the-bone-marrow-of-breast-cancer-patients-selectively-upregulate-the-emigration-receptor-s1p1
#16
Anchana Rathinasamy, Christoph Domschke, Yingzi Ge, Hans-Henning Böhm, Steffen Dettling, David Jansen, Felix Lasitschka, Ludmila Umansky, Markus H Gräler, Jennifer Hartmann, Christel Herold-Mende, Florian Schuetz, Philipp Beckhove
Regulatory T cells (Treg) hamper anti-tumor T-cell responses resulting in reduced survival and failure of cancer immunotherapy. Among lymphoid organs, the bone marrow (BM) is a major site of Treg residence and recirculation. However, the process governing the emigration of Treg from BM into the circulation remains elusive. We here show that breast cancer patients harbour reduced Treg frequencies in the BM as compared to healthy individuals or the blood. This was particularly the case for tumor antigen-specific Treg which were quantified by MHCII tumor peptide loaded tetramers...
February 21, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28218904/the-protumorigenic-potential-of-fty720-by-promoting-extramedullary-hematopoiesis-and-mdsc-accumulation
#17
Y Li, T Zhou, Y Wang, C Ning, Z Lv, G Han, J C Morris, E N Taylor, R Wang, H Xiao, C Hou, Y Ma, B Shen, J Feng, R Guo, Y Li, G Chen
FTY720 (also called fingolimod) is recognized as an immunosuppressant and has been approved by the Food and Drug Administration to treat refractory multiple sclerosis. However, long-term administration of FTY720 potentially increases the risk for cancer in recipients. The underlying mechanisms remain poorly understood. Herein, we provided evidence that FTY720 administration potentiated tumor growth. Mechanistically, FTY720 enhanced extramedullary hematopoiesis and massive accumulation of myeloid-derived suppressor cells (MDSCs), which actively suppressed antitumor immune responses...
February 20, 2017: Oncogene
https://www.readbyqxmd.com/read/28191815/bladder-cancer-cell-growth-and-motility-implicate-cannabinoid-2-receptor-mediated-modifications-of-sphingolipids-metabolism
#18
Arianna Bettiga, Massimo Aureli, Giorgia Colciago, Valentina Murdica, Marco Moschini, Roberta Lucianò, Daniel Canals, Yusuf Hannun, Petter Hedlund, Giovanni Lavorgna, Renzo Colombo, Rosaria Bassi, Maura Samarani, Francesco Montorsi, Andrea Salonia, Fabio Benigni
The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC). CB expression on human normal and BC specimens was tested by immunohistochemistry. Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling. CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28191010/role-of-dietary-metabolites-in-regulating-the-host-immune-response-in-gastrointestinal-disease
#19
REVIEW
Mohamad El-Zaatari, John Y Kao
The host immune response to gastrointestinal (GI) infections, hypersensitivity reactions, or GI cancers comprises numerous pathways that elicit responses on different host cells. Some of these include (1) the stimulation of mast cells via their IgE receptor, (2) the production of antibodies leading to antibody-mediated cytotoxic T/natural killer cell killing, (3) the activation of the complement pathway, and (4) the activation of the adaptive immune response via antigen-presenting cell, T cell, and B cell interactions...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28178265/computational-investigation-of-sphingosine-kinase-1-sphk1-and-calcium-dependent-erk1-2-activation-downstream-of-vegfr2-in-endothelial-cells
#20
Hojjat Bazzazi, Aleksander S Popel
Vascular endothelial growth factor (VEGF) is a powerful regulator of neovascularization. VEGF binding to its cognate receptor, VEGFR2, activates a number of signaling pathways including ERK1/2. Activation of ERK1/2 is experimentally shown to involve sphingosine kinase 1 (SphK1) activation and its calcium-dependent translocation downstream of ERK1/2. Here we construct a rule-based computational model of signaling downstream of VEGFR2, by including SphK1 and calcium positive feedback mechanisms, and investigate their consequences on ERK1/2 activation...
February 2017: PLoS Computational Biology
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