Molecular Mechanisms of Regulation and Modulation of Sphingosine Kinase 1 Activity in Cancer

癌症中鞘氨醇激酶 1 活性调控的分子机制

• 批准号: 9123143
• 负责人: Michael John Pulkoski-Gross
• 金额: $ 3.34万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123143
• 关键词: Acetates; Active Sites; Affect; Apoptosis; Apoptotic; Area; Arginine; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Biology; Breast; Cancer Biology; Cancer Etiology; Cancer Patient; Cancer cell line; Catalysis; Cause of Death; Cell Survival; Cell membrane; Cells; Cellular biology; Ceramides; Charge; Colon; Development; Disease; Electrostatics; Enzymes; Equilibrium; FDA approved; Fluorescence; Future; Glare; Glioblastoma; Goals; In Vitro; Investigation; Knowledge; Link; Lipids; Liposomes; Lung; Lysine; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Mediating; Membrane; Metabolism; Molecular; Monitor; Neoplasm Metastasis; Pathway interactions; Phosphatidic Acid; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phospholipid Metabolism; Phospholipids; Phosphorylation; Phosphotransferases; Play; Production; Property; Prostate; Proteins; Regulation; Renal Cell Carcinoma; Research; Role; SPHK1 enzyme; Signal Transduction; Site; Small Interfering RNA; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Structure; Surface; Techniques; Testing; Therapeutic; Tumor Volume; United States; United States Food and Drug Administration; Work; Xenograft Model; angiogenesis; base; biophysical techniques; blood vessel development; cancer cell; cancer therapy; cancer type; cell growth; cell motility; drug development; ezrin; inhibitor/antagonist; inorganic phosphate; knock-down; malignant breast neoplasm; migration; mutant; novel; outcome forecast; overexpression; phorbol-12-myristate; public health relevance; response; sensor; sphingosine 1-phosphate; sphingosine kinase; structural biology; tumor progression

 DESCRIPTION (provided by applicant): The central goal of this proposal is to understand how sphingosine kinase 1 (SK1) is regulated in order to build better inhibitors as alternative cancer therapeutics. SK1 is an important enzyme in the sphingolipid metabolism pathway as it sits between the pro-apoptotic sphingolipids ceramide and sphingosine and the pro- survival and pro-angiogenic lipid sphingosine-1-phosphate (S1P). S1P has been shown to have both intra- and inter-cellular signaling properties that play an important role in angiogenesis and invasion. SK1 has been detected in numerous different cancer types and cell lines. Additionally, SK1 activity has been shown to be over-expressed in several different cancer types. SK1 activity has been previously shown to be modulated by anionic phospholipids (APLs) which can be found in the plasma membrane of all cells. Furthermore, it has been shown that SK1 can translocate to the plasma membrane where its substrate is located. Despite the strong underlying support for the roles of SK1 and S1P in cancer, there is a lack in understanding of the molecular mechanisms that control SK1 activation and ultimately S1P levels. Based on these premises, we seek in Specific Aim 1 to determine the molecular mechanism of SK1 activation by APLs, both in vitro, in cells, and through structural biology, which we suggest is mediated through a novel APL binding site. Additionally, we will look at the effects of the SK1 membrane binding mutants on S1P-mediated cancer biological responses including phosphorylation of the migration and invasion associated protein Ezrin. Furthermore, I have identified novel interactions between SK1 and phosphatidylinositol phosphates (PIPs) which can also be found at the plasma membrane. I have shown that certain PIPs can de-activate SK1 even in the presence of activating APLs. This proposal, in specific Aim 2, aims at understanding these interaction and their biological consequences to cancer cell invasion and angiogenesis. Currently, there are no inhibitors of SK1 approved by the U.S. Food and Drug Administration for the treatment of any disease. Therefore, there is a need for the development of SK1 inhibitors as alternative therapeutic options for cancer. The overarching goal of these studies is to understand the molecular mechanism of SK1 activation by APLs and how PIPs can affect SK1 activity. Understanding the mechanisms by which SK1 activity is allosterically modulated will open the door to a new class of SK1 inhibitors which target SK1s ability to bind to the membrane, therefore limiting its access to its substrate. Targeting S1P production allows for a new avenue of anti-cancer therapies.

 描述（由适用提供）：该提案的核心目标是了解如何调节鞘氨醇激酶1（SK1），以建立更好的抑制剂作为替代性癌症治疗。 SK1是鞘脂代谢途径中的重要酶，因为它位于神经酰胺和鞘氨醇的促凋亡鞘脂之间，以及促卵巢和亲苏硫化剂和促血管生成的脂质鞘氨碱-1-磷酸（S1P）。 S1P已被证明具有在血管生成和侵袭中起重要作用的细胞内信号传导特性。已经在许多不同的癌症类型和细胞系中检测到SK1。另外，SK1活性已显示在几种不同的癌症类型中过表达。先前已证明SK1活性是由阴离子磷脂（APL）调节的，可以在所有细胞的质膜中找到。此外，已经表明SK1可以转移到其底物所在的质膜。尽管对SK1和S1P在癌症中的作用有强烈的支持，但缺乏了解控制SK1激活和最终S1P水平的分子机制。基于这些前提，我们在特定目标1中寻求确定APLS在体外，细胞和结构生物学中的SK1激活的分子机制，我们建议通过新型的APL结合位点介导。此外，我们将研究SK1膜结合突变体对S1P介导的癌症生物学反应的影响，包括迁移和侵袭相关蛋白Ezrin的磷酸化。此外，我已经确定了SK1和磷脂酰肌醇磷酸盐（PIP）之间的新型相互作用，这些相互作用也可以在质膜上找到。我已经表明，即使在存在激活APL的情况下，某些PIP也可以使SK1失活。该建议在特定的目标2中旨在了解这些相互作用及其对癌细胞侵袭和血管生成的生物学后果。目前，没有美国食品药品监督管理局批准的任何疾病的SK1抑制剂。因此，需要开发SK1抑制剂作为癌症的替代治疗选择。这些研究的总体目标是了解APLS激活SK1激活的分子机制，以及PIPS如何影响SK1活性。了解SK1活性在变构中的机制将打开新类别的SK1抑制剂的门，该SK1抑制剂的目标是SK1S与膜结合的能力，从而限制了其对基质的访问。靶向S1P生产允许新的抗癌疗法途径。