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SphK1/S1P
S1P
S1P(4)
The SphK1/S1P pathway elicits various cellular processes including cell proliferation, cell survival, or angiogenesis, as a new modulator of HIF-1A activity under hypoxic conditions.(1) S1P is a signaling sphingolipid also known as lysosphingolipid, characterized by an aliphatic aminoalcohol, sphingosine. S1P is an extracellular ligand for G protein-coupled receptor S1PR1. S1P is a blood borne lipid mediator, in particular in association with lipoproteins such as high density lipoprotein. S1P seems to have biological significance in immune cell trafficking. S1P also modulates the proliferation of skin cells. While S1P suppresses epidermal proliferation as the glucocorticoids do, it differs from them in so far, as proliferation of dermal fibroblasts is not reduced. S1P activates fibroblast-derived ECM protein production. In the immune system, it is a major regulator of trafficking of T- and B-cells. S1P interaction with its receptor S1PR1 is needed for the egress of immune cells from the thymus and lymph nodes into the lymphatic vessels. Inhibition of S1P receptors was shown to be critical for immunomodulation. Sphingosine can be released from ceramides, a process catalyzed by the enzyme ceramidase. Phosphorylation of sphingosine is catalyzed by SK, an enzyme ubiquitously found in the cytosol and endoplasmatic reticulum of various types of cells. S1P can be dephosphorylated to sphingosine by sphingosine phosphatases and can be irreversibly degraded by an enzyme, sphingosine phosphate lyase.(2)
The levels of S1P are 5 to 10 times up-regulated in ovarian cancer patients. S1P at this physiological concentration stimulates migration and invasion of epithelial ovarian cancer cells but inhibits migration of normal ovarian surface epithelial cells.(3) Most ovarian cancers arise from the epithelium of the ovary. Therefore, extracellular S1P could have an important role in cancer progression by promoting migration of epithelial ovarian cancer cells.(2)

Drugs/Indications
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
sonepcizumab LT1009 Asonep Lpath P2: RCC; P1: solid trials
trials
trials
ABC294640      Apogee  P1/2: lymphoma; P1: Pancreatic, solid trials



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References

1. Ader I MB, Cuvillier O. When the sphingosine kinase 1/sphingosine 1-phosphate pathway meets hypoxia signaling: new targets for cancer therapy. Cancer Res. 2009;69(9):3723-6. PMCID: 19383898.

2. Sphingosine-1-phosphate. [cited]; Available from: http://en.wikipedia.org/wiki/Sphingosine-1-phosphate.

3. Wang D, Zhao Z, Caperell-Grant A, Yang G, Mok SC, Liu J, et al. S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells. Molecular cancer therapeutics. 2008;7(7):1993-2002.

4. Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. Journal of Cell Science. 2005;118(20):4605-12.