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S1P Cancer

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https://www.readbyqxmd.com/read/28081222/at7867-inhibits-human-colorectal-cancer-cells-via-akt-dependent-and-akt-independent-mechanisms
#1
Shihu Zhang, Zhengming Deng, Chen Yao, Ping Huang, Yi Zhang, Shibing Cao, Xiangcheng Li
AKT is often hyper-activated in human colorectal cancers (CRC). This current study evaluated the potential anti-CRC activity by AT7867, a novel AKT and p70S6K1 (S6K1) dual inhibitor. We showed that AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. Meanwhile, it provoked caspase-dependent apoptosis in the CRC cells. Molecularly, AT7867 blocked AKT-S6K1 activation in CRC cells. Restoring AKT-S6K1 activation, via expression of a constitutively-active AKT1 ("ca-AKT1"), only partially attenuated AT7867-induced HT-29 cell death...
2017: PloS One
https://www.readbyqxmd.com/read/28075451/the-role-of-sphingolipid-signalling-in-diabetes%C3%A2-associated-pathologies-review
#2
Mei Li Ng, Carol Wadham, Olga A Sukocheva
Sphingosine kinase (SphK) is an important signalling enzyme that catalyses the phosphorylation of sphingosine (Sph) to form sphingosine‑1‑phosphate (S1P). The multifunctional lipid, S1P binds to a family of five G protein-coupled receptors (GPCRs). As an intracellular second messenger, S1P activates key signalling cascades responsible for the maintenance of sphingolipid metabolism, and has been implicated in the progression of cancer, and the development of other inflammatory and metabolic diseases...
January 11, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28054036/sphingosine-1-phosphate-in-the-lymphatic-fluid-determined-by-novel-methods
#3
Masayuki Nagahashi, Akimitsu Yamada, Tomoyoshi Aoyagi, Jeremy Allegood, Toshifumi Wakai, Sarah Spiegel, Kazuaki Takabe
BACKGROUND: Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that regulates many physiological and pathological processes. It has been suggested that S1P gradient with high concentrations in the blood and lymphatic fluid and low concentrations in the peripheral tissue plays important roles in immune cell trafficking and potentially cancer progression. However, only a few reports have assessed S1P levels in the lymphatic fluid due to lack of an established easy-to-use method...
December 2016: Heliyon
https://www.readbyqxmd.com/read/28052056/genome-wide-in-vivo-screen-identifies-novel-host-regulators-of-metastatic-colonization
#4
Louise van der Weyden, Mark J Arends, Andrew D Campbell, Tobias Bald, Hannah Wardle-Jones, Nicola Griggs, Martin Del Castillo Velasco-Herrera, Thomas Tüting, Owen J Sansom, Natasha A Karp, Simon Clare, Diane Gleeson, Edward Ryder, Antonella Galli, Elizabeth Tuck, Emma L Cambridge, Thierry Voet, Iain C Macaulay, Kim Wong, Sanger Mouse Genetics Project, Sarah Spiegel, Anneliese O Speak, David J Adams
Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment ('host', which includes stromal cells and the immune system). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth ('colonization') being critical in determining metastatic outcome...
January 4, 2017: Nature
https://www.readbyqxmd.com/read/28036019/lymph-nodes-and-cancer-metastasis-new-perspectives-on-the-role-of-intranodal-lymphatic-sinuses
#5
REVIEW
Rui-Cheng Ji
The lymphatic system is essential for transporting interstitial fluid, soluble antigen, and immune cells from peripheral tissues to lymph nodes (LNs). Functional integrity of LNs is dependent on intact lymphatics and effective lymph drainage. Molecular mechanisms that facilitate interactions between tumor cells and lymphatic endothelial cells (LECs) during tumor progression still remain to be identified. The cellular and molecular structures of LNs are optimized to trigger a rapid and efficient immune response, and to participate in the process of tumor metastasis by stimulating lymphangiogenesis and establishing a premetastatic niche in LNs...
December 28, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27956387/targeting-sphingosine-kinase-1-induces-mcl1-dependent-cell-death-in-acute-myeloid-leukemia
#6
Jason A Powell, Alexander C Lewis, Wenying Zhu, John Toubia, Melissa R Pitman, Craig T Wallington-Beddoe, Paul A B Moretti, Diana Iarossi, Saumya E Samaraweera, Nik Cummings, Hayley S Ramshaw, Daniel Thomas, Andrew H Wei, Angel F Lopez, Richard J D'Andrea, Ian D Lewis, Stuart M Pitson
Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1-phosphate (S1P) and has established roles in tumor initiation, progression and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells...
December 12, 2016: Blood
https://www.readbyqxmd.com/read/27829348/in-silico-identification-of-novel-orthosteric-inhibitors-of-sphingosine-kinase-1-sk1
#7
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
https://www.readbyqxmd.com/read/27825124/acid-ceramidase-is-upregulated-in-aml-and-represents-a-novel-therapeutic-target
#8
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
https://www.readbyqxmd.com/read/27811358/sphk1-promotes-breast-epithelial-cell-proliferation-via-nf-%C3%AE%C2%BAb-p65-mediated-cyclin-d1-expression
#9
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
https://www.readbyqxmd.com/read/27800303/sphingosine-1-phosphate-a-new-modulator-of-immune-plasticity-in-the-tumor-microenvironment
#10
REVIEW
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
https://www.readbyqxmd.com/read/27779706/effect-of-colorectal-cancer-on-the-number-of-normal-stem-cells-circulating-in-peripheral-blood
#11
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...
December 2016: Oncology Reports
https://www.readbyqxmd.com/read/27727447/a-phase-2-study-of-the-sphingosine-1-phosphate-antibody-sonepcizumab-in-patients-with-metastatic-renal-cell-carcinoma
#12
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
https://www.readbyqxmd.com/read/27696512/melatonin-prevents-deregulation-of-the-sphingosine-kinase-sphingosine-1-phosphate-signaling-pathway-in-a-mouse-model-of-diethylnitrosamine-induced-hepatocellular-carcinoma
#13
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)/sphingosine 1-phosphate (S1P) pathway is involved in multiple biological processes, including carcinogenesis. Melatonin shows beneficial effects in cell and animal models of hepatocellular carcinoma, 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 the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight i.p) once a week for 8 weeks...
January 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/27664902/host-sphingosine-kinase-1-worsens-pancreatic-cancer-peritoneal-carcinomatosis
#14
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
https://www.readbyqxmd.com/read/27663260/to-fingolimod-and-beyond-the-rich-pipeline-of-drug-candidates-that-target-s1p-signaling
#15
REVIEW
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
https://www.readbyqxmd.com/read/27634386/sphingosylphosphorylcholine-regulates-the-hippo-signaling-pathway-in-a-dual-manner
#16
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
https://www.readbyqxmd.com/read/27622075/distinct-mechanisms-of-b-and-t-lymphocyte-accumulation-generate-tumor-draining-lymph-node-hypertrophy
#17
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
https://www.readbyqxmd.com/read/27621003/breast-cancer-sphingosine-1-phosphate-is-associated-with-phospho-sphingosine-kinase-1-and-lymphatic-metastasis
#18
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
https://www.readbyqxmd.com/read/27616330/upregulation-of-the-s1p3-receptor-in-metastatic-breast-cancer-cells-increases-migration-and-invasion-by-induction-of-pge2-and-ep2-ep4-activation
#19
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
https://www.readbyqxmd.com/read/27588496/an-oncogenic-role-for-sphingosine-kinase-2
#20
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...
October 4, 2016: Oncotarget
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