Sphingosine 1-Phosphate, a Specific Endogenous Signaling Molecule Controlling Cell Motility and Tumor Cell Invasiveness

• Published in: Proceedings of the National Academy of Sciences - PNAS 1992-10, Vol.89 (20), p.9686-9690
• Main Authors: Sadahira, Yoshito, Ruan, Fuqiang, Hakomori, Sen-itiroh, Igarashi, Yasuyuki
• Format: Article
• Language: English
• Subjects: 3T3 cells; Animals; Cell Division - drug effects; Cell growth; Cell lines; Cell motility; Cell Movement - drug effects; Cells; Cellular biology; Cultured cells; Endothelial cells; Humans; In Vitro Techniques; Lysophospholipids; Melanoma; metastases; Mice; Molecules; motility; Neoplasm Invasiveness; Protein Kinase C - physiology; role; Second Messenger Systems; signal transduction; Sphingolipids - pharmacology; Sphingolipids - physiology; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine - pharmacology; sphingosine 1-phosphate; Tumor cell line; Tumor Cells, Cultured; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.89.20.9686

Sphingosine 1-phosphate (Sph-1-P), the initial product of Sph degradation by Sph kinase, was shown to be a strong inhibitor of cell motility and phagokinesis of B16 melanoma and other types of cells at 10-100 nM concentration. It also inhibited "chemoinvasion' of tumor cells through a thick layer of Matrigel on a filter membrane. Such inhibitory effects were produced minimally or not at all by Sph, N-methyl derivatives of Sph, or other related sphingolipids and phospholipids. Sph-1-P did not inhibit cell proliferation or protein kinase C (PKC) activity, in contrast to Sph and N-methyl-Sph, which inhibit PKC activity and cell growth in general. Radiolabeled [3H] Sph and [14C] N-methyl-Sph were rapidly incorporated into B16 melanoma cells. However,[14C] N-methyl-Sph was not metabolically converted into other compounds, whereas [3H] Sph was efficiently converted within 10 min to Sph-1-P, followed by conversion to other sphingolipids and phospholipids. The inhibitory effect of Sph-1-P on cell motility and tumor cell invasiveness could be a specific phenomenon independent of PKC and other known transmembrane signaling mechanisms, based on an unknown mechanism. It may directly affect organizational assembly of actin filaments. Since exogenous Sph is rapidly converted into Sph-1-P, some reported effects of Sph may be ascribable to such conversion.