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Targeting sphingosine-1-phosphate receptors in cancer.

ABSTRACT: Sphingosine 1-phosphate (S1P) is a bioactive lipid with diverse biological functions, including cell proliferation, differentiation, angiogenesis, chemotaxis, and migration. Many of the activities of S1P are mediated through five closely related G-protein-coupled receptors of the sphingosine-1-phosphate receptor family (S1PR) which play a crucial role in sphingolipid metabolism. Each of these receptors appears to be tissue specific and to have demonstrated roles in the regulation of cell proliferation and survival in various cancer types. Further analysis of the function that S1PRs serve in hematological malignancies offers a great potential for the discovery of novel and selective therapeutic agents targeting these receptors. This review focuses on the characterization of S1PRs and their roles in cancer development in various signaling pathways mediated through specific G coupled protein. In particular, pharmacological agents targeting these S1PRs will be discussed and their potential will be examined.

SUBMITTER: Watters RJ

PROVIDER: S-EPMC3698949 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Targeting sphingosine-1-phosphate receptors in cancer.

Watters Rebecca J RJ Wang Hong-Gang HG Sung Shen-Shu SS Loughran Thomas P TP Liu Xin X

Anti-cancer agents in medicinal chemistry 20111101 9

Sphingosine 1-phosphate (S1P) is a bioactive lipid with diverse biological functions, including cell proliferation, differentiation, angiogenesis, chemotaxis, and migration. Many of the activities of S1P are mediated through five closely related G-protein-coupled receptors of the sphingosine-1-phosphate receptor family (S1PR) which play a crucial role in sphingolipid metabolism. Each of these receptors appears to be tissue specific and to have demonstrated roles in the regulation of cell prolife ...[more]

PMID: 21707490

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Project description:BackgroundSphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts through a family of five G-protein-coupled receptors (S1PR1-5) and plays a key role in regulating the inflammatory response. Our previous studies demonstrated that rat sensory neurons express the mRNAs for all five S1PRs and that S1P increases neuronal excitability primarily, but not exclusively, through S1PR1. This raises the question as to which other S1PRs mediate the enhanced excitability.MethodsIsolated sensory neurons were treated with either short-interfering RNAs (siRNAs) or a variety of pharmacological agents targeted to S1PR1/R2/R3 to determine the role(s) of these receptors in regulating neuronal excitability. The excitability of isolated sensory neurons was assessed by using whole-cell patch-clamp recording to measure the capacity of these cells to fire action potentials (APs).ResultsAfter siRNA treatment, exposure to S1P failed to augment the excitability. Pooled siRNA targeted to S1PR1 and R3 also blocked the enhanced excitability produced by S1P. Consistent with the siRNA results, pretreatment with W146 and CAY10444, selective antagonists for S1PR1 and S1PR3, respectively, prevented the S1P-induced increase in neuronal excitability. Similarly, S1P failed to augment excitability after pretreatment with either VPC 23019, which is a S1PR1 and R3 antagonist, or VPC 44116, the phosphonate analog of VPC 23019. Acute exposure (10 to 15 min) to either of the well-established functional antagonists, FTY720 or CYM-5442, produced a significant increase in the excitability. Moreover, after a 1-h pretreatment with FTY720 (an agonist for S1PR1/R3/R4/R5), neither SEW2871 (S1PR1 selective agonist) nor S1P augmented the excitability. However, after pretreatment with CYM-5442 (selective for S1PR1), SEW2871 was ineffective, but S1P increased the excitability of some, but not all, sensory neurons.ConclusionsThese results demonstrate that the enhanced excitability produced by S1P is mediated by activation of S1PR1 and/or S1PR3.

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Targeting sphingosine-1-phosphate receptors in cancer.

Publications

Targeting sphingosine-1-phosphate receptors in cancer.

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