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S1P Cancer

Ozge Bayraktar, Elif Ozkirimli, Kutlu O Ulgen
Sphingosine kinase 1 (SK1) overexpression and elevated sphingosine-1-phosphate (S1P) levels have been correlated with many disease states from cancer to inflammatory diseases to diabetes. Even though the discovery of SK1 inhibitors has been considered as effective chemotherapeutic agents, poor potency, lack of selectivity and poor pharmacokinetic properties have been major problems in the first generation SK1 inhibitors. Thus, there is an urgent need for the discovery of in vivo stable selective SK1 inhibitors with improved potency...
November 7, 2016: Current Protein & Peptide Science
Su-Fern Tan, Xin Liu, Todd E Fox, Brian M Barth, Arati Sharma, Stephen D Turner, Andy Awwad, Alden Dewey, Kenichiro Doi, Barbara Spitzer, Mithun Vinod Shah, Samy A F Morad, Dhimant Desai, Shantu Amin, Junjia Zhu, Jason Liao, Jong Yun, Mark Kester, David F Claxton, Hong-Gang Wang, Myles C Cabot, Edward H Schuchman, Ross L Levine, David J Feith, Thomas P Loughran
There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity...
November 4, 2016: Oncotarget
Shifei Li, Yan Zhou, Xiaodong Zheng, Xiujuan Wu, Yueyang Liang, Shushu Wang, Yi Zhang
Lipid metabolism is crucially involved with the promotion of malignant progression and metastasis in various cancers. Growing evidence suggests that many types of cancers express high levels of sphingosine kinase 1 (Sphk1), which is known to mediate cell proliferation We hypothesized that Sphk1/sphingosine-1-phosphate (S1P) signaling contributes to tumor progression. In MCF10A and MCF10A-Sphk1 breast epithelial cells, we used TNF-α to activate the Sphk1/S1P pathway and the measured expression levels of NF-κBp65 and cyclin D1 mRNA and protein in the presence and absence of an NF-κB-p65 inhibitor...
November 2, 2016: Oncotarget
Yamila I Rodriguez, Ludmila E Campos, Melina G Castro, Ahmed Aladhami, Carole A Oskeritzian, Sergio E Alvarez
In the last 15 years, increasing evidences demonstrate a strong link between sphingosine-1-phosphate (S1P) and both normal physiology and progression of different diseases, including cancer and inflammation. Indeed, numerous studies show that tissue levels of this sphingolipid metabolite are augmented in many cancers, affecting survival, proliferation, angiogenesis, and metastatic spread. Recent insights into the possible role of S1P as a therapeutic target has attracted enormous attention and opened new opportunities in this evolving field...
2016: Frontiers in Oncology
Wojciech Marlicz, Katarzyna Sielatycka, Karol Serwin, Ewa Kubis, Marta Tkacz, Rafał Głuszko, Andrzej Białek, Teresa Starzyńska, Mariusz Z Ratajczak
Bone marrow (BM) residing stem cells are mobilized from their BM niches into peripheral blood (PB) in several pathological situations including tissue organ injury and systemic inflammation. We recently reported that the number of BM-derived stem cells (SCs) increases in patients with pancreatic and stomach cancer. Accordingly, we observed higher numbers of circulating very small embryonic/epiblast‑like stem cells (VSELs) and mesenchymal stem cells (MSCs) that were associated with the activation of pro-mobilizing complement cascade and an elevated level of sphingosine-1 phosphate (S1P) in PB plasma...
October 18, 2016: Oncology Reports
Sumanta K Pal, Harry A Drabkin, James A Reeves, John D Hainsworth, Susan E Hazel, Dario A Paggiarino, Jon Wojciak, Gary Woodnutt, Rupal S Bhatt
BACKGROUND: Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy. METHODS: Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent...
October 11, 2016: Cancer
Diana I Sánchez, Bárbara González-Fernández, Beatriz San-Miguel, Juan Ortiz de Urbina, Irene Crespo, Javier González-Gallego, María J Tuñón
The sphingosine kinase (SphK)/sphingosine1-phosphate (S1P) pathway is involved in multiple biological processes, including carcinogenesis. Melatonin shows beneficial effects in cell and animal models of hepatocellular carcinoma (HCC), but it is unknown if they are associated with the modulation of the SphK/S1P system, along with different downstream signaling pathways modified in cancer. We investigated effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight i.p) once a week for 8 weeks...
October 1, 2016: Journal of Pineal Research
Hiroaki Aoki, Masayo Aoki, Eriko Katsuta, Rajesh Ramanathan, Michael O Idowu, Sarah Spiegel, Kazuaki Takabe
BACKGROUND: There are no effective treatments for pancreatic cancer peritoneal carcinomatosis (PC) or cancer dissemination in abdominal cavity. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by sphingosine kinases (SphK1 and SphK2), plays critical roles in cancer progression. We reported that SphK1, but not SphK2, is responsible for S1P export from breast cancer cells and recently discovered that S1P is linked to inflammation and cancer in colitis-associated cancer progression...
October 2016: Journal of Surgical Research
Wee Siong Chew, Wei Wang, Deron R Herr
Sphingosine 1-phosphate (S1P) is an extracellular lipid signaling molecule that acts as a selective, high-affinity ligand for a family of five G protein-coupled receptors. This signaling system was first identified twenty years ago, and has since been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer. The therapeutic potential of targeting this system took center stage when it was demonstrated that the immune modulator, fingolimod (FTY720/Gilenya), exerts it lymphopenic effect by acting on S1P receptors, primarily on S1P receptor 1 (S1P1)...
November 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Kati Kemppainen, Nina Wentus, Taru Lassila, Asta Laiho, Kid Törnquist
Sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid which regulates many cancer-related processes, including cellular proliferation. The Hippo signaling pathway consists of a cascade of tumor suppressive kinases Mst1/2 and Lats1/2 and their downstream targets YAP and TAZ which are generally pro-proliferative transcriptional regulators. Direct phosphorylation by Lats1/2 causes inhibition or degradation of YAP/TAZ and down-regulation of their target genes. We found SPC treatment of MDA-MB-435S breast cancer cells to strongly inhibit their proliferation and to induce a sustained Lats2 protein expression (6-24h)...
December 2016: Cellular Signalling
Lauren M Habenicht, Tina C Albershardt, Brian M Iritani, Alanna Ruddell
Tumor-draining lymph nodes (TDLNs) often enlarge in human cancer patients and in murine tumor models, due to lymphocyte accumulation and lymphatic sinus growth. B lymphocytes within TDLNs can drive lymph node hypertrophy in response to tumor growth, however little is known about the mechanisms directing the preferential accumulation of B lymphocytes relative to T cells in enlarging TDLNs. To define why B and T lymphocytes accumulate in TDLNs, we quantified lymphocyte proliferation, apoptosis, entry, and exit in TDLNs versus contralateral non-TDLNs (NTDLNs) in a footpad B16-F10 melanoma mouse model...
August 2016: Oncoimmunology
Junko Tsuchida, Masayuki Nagahashi, Masato Nakajima, Kazuki Moro, Kumiko Tatsuda, Rajesh Ramanathan, Kazuaki Takabe, Toshifumi Wakai
BACKGROUND: Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, has been implicated as a key regulatory molecule in cancer through its ability to promote cell proliferation, migration, angiogenesis, and lymphangiogenesis. Previous studies suggested that S1P produced by sphingosine kinase 1 (SphK1) in breast cancer plays important roles in progression of disease and metastasis. However, the associations between S1P and clinical parameters in human breast cancer have not been well investigated to date...
September 2016: Journal of Surgical Research
Iuliia Filipenko, Stephanie Schwalm, Luca Reali, Josef Pfeilschifter, Doriano Fabbro, Andrea Huwiler, Uwe Zangemeister-Wittke
Breast cancer is one of the most common and devastating malignancies among women worldwide. Recent evidence suggests that malignant progression is also driven by processes involving the sphingolipid molecule sphingosine 1-phosphate (S1P) and its binding to cognate receptor subtypes on the cell surface. To investigate the effect of this interaction on the metastatic phenotype, we used the breast cancer cell line MDA-MB-231 and the sublines 4175 and 1833 derived from lung and bone metastases in nude mice, respectively...
November 2016: Biochimica et Biophysica Acta
Heidi A Neubauer, Duyen H Pham, Julia R Zebol, Paul A B Moretti, Amanda L Peterson, Tamara M Leclercq, Huasheng Chan, Jason A Powell, Melissa R Pitman, Michael S Samuel, Claudine S Bonder, Darren J Creek, Briony L Gliddon, Stuart M Pitson
While both human sphingosine kinases (SK1 and SK2) catalyze the generation of the pleiotropic signaling lipid sphingosine 1-phosphate, these enzymes appear to be functionally distinct. SK1 has well described roles in promoting cell survival, proliferation and neoplastic transformation. The roles of SK2, and its contribution to cancer, however, are much less clear. Some studies have suggested an anti-proliferative/pro-apoptotic function for SK2, while others indicate it has a pro-survival role and its inhibition can have anti-cancer effects...
August 30, 2016: Oncotarget
A N McCracken, R J McMonigle, J Tessier, R Fransson, M S Perryman, B Chen, A Keebaugh, E Selwan, S A Barr, S M Kim, S G Roy, G Liu, D Fallegger, L Sernissi, C Brandt, N Moitessier, A J Snider, S Clare, M Müschen, A Huwiler, M T Kleinman, S Hanessian, A L Edinger
The frequency of poor outcomes in relapsed leukemia patients underscores the need for novel therapeutic approaches. The FDA-approved immunosuppressant FTY720 limits leukemia progression by activating protein phosphatase 2A and restricting nutrient access. Unfortunately, FTY720 cannot be re-purposed for use in cancer patients due to on-target toxicity associated with S1P receptor activation at the elevated, anti-neoplastic dose. Here we show that the constrained azacyclic FTY720 analog SH-RF-177 lacks S1P receptor activity but maintains anti-leukemic activity in vitro and in vivo...
August 30, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Masayuki Nagahashi, Junko Tsuchida, Kazuki Moro, Miki Hasegawa, Kumiko Tatsuda, Ingrid A Woelfel, Kazuaki Takabe, Toshifumi Wakai
BACKGROUND: Sphingolipids, including sphingosine-1-phosphate (S1P) and ceramide, have emerged as key regulatory molecules that control various aspects of cell growth and proliferation in cancer. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients have yet to be determined. The aims of this study were to determine the levels of sphingolipids including S1P, ceramides, and other sphingolipids, in breast cancer and normal breast tissue and to compare the difference in levels of each sphingolipid between the two tissues...
August 2016: Journal of Surgical Research
Kevin R Lynch, S Brandon Thorpe, Webster L Santos
Sphingosine kinase (SphK1 & SphK2) is the sole source of the pleiotropic lipid mediator, sphingosine-1-phosphate (S1P). S1P has been implicated in a variety of diseases such as cancer, Alzheimer's disease, sickle cell disease and fibrosis and thus the biosynthetic route to S1P is a logical target for drug discovery. Areas covered: In this review, the authors consider the SphK inhibitor patent literature from 2006-2016 Q1 with the emphasis on composition of matter utility patents. The Espacenet database was queried with the search term 'sphingosine AND kinase' to identify relevant literature...
December 2016: Expert Opinion on Therapeutic Patents
Cécile Gstalder, Isabelle Ader, Olivier Cuvillier
Clear cell renal cell carcinoma (ccRCC) is characterized by intratumoral hypoxia and chemoresistance. The hypoxia-inducible factors HIF1α and HIF2α play a crucial role in ccRCC initiation and progression. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF1α and HIF2α under hypoxia in various cancer cell models. Here, we report that FTY720, an inhibitor of the S1P signaling pathway, inhibits both HIF1α and HIF2α accumulation in several human cancer cell lines...
October 2016: Molecular Cancer Therapeutics
Jose Felix Moruno Manchon, Ndidi-Ese Uzor, Steven Finkbeiner, Andrey S Tsvetkov
Although implicated in neurodegeneration, autophagy has been characterized mostly in yeast and mammalian non-neuronal cells. In a recent study, we sought to determine if SPHK1 (sphingosine kinase 1), implicated previously in macroautophagy/autophagy in cancer cells, regulates autophagy in neurons. SPHK1 synthesizes sphingosine-1-phosphate (S1P), a bioactive lipid involved in cell survival. In our study, we discovered that, when neuronal autophagy is pharmacologically stimulated, SPHK1 relocalizes to the endocytic and autophagic organelles...
August 2, 2016: Autophagy
C Evangelisti, C Evangelisti, F Buontempo, A Lonetti, E Orsini, F Chiarini, J T Barata, S Pyne, N J Pyne, A M Martelli
Sphingolipids, such as ceramide, sphingosine and sphingosine 1-phosphate (S1P) are bioactive molecules that have important functions in a variety of cellular processes, which include proliferation, survival, differentiation and cellular responses to stress. Sphingolipids have a major impact on the determination of cell fate by contributing to either cell survival or death. Although ceramide and sphingosine are usually considered to induce cell death, S1P promotes survival of cells. Sphingosine kinases (SPHKs) are the enzymes that catalyze the conversion of sphingosine to S1P...
November 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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