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Cross-talk between LPA₁ and Epidermal Growth Factor Receptors Mediates Up-regulation of Sphingosine Kinase 1 to Promote Gastric Cancer Cell Motility and Invasion

¹ Department of Biochemistry and Molecular Biology and the Massey Cancer Center and ² Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia; and ³ National Institute of Mental Health, Bethesda, Maryland

Requests for reprints: Sarah Spiegel, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298-0614. Phone: 804-828-9330; Fax: 804-828-8999; E-mail: sspiegel{at}vcu.edu.

Key Words: lysophosphatidic acid • sphingosine-1-phosphate • sphingosine kinase type 1 • EGF • EGFR transactivation

Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are lysophospholipid mediators of diverse cellular processes important for cancer progression. S1P is produced by two sphingosine kinases, SphK1 and SphK2. Expression of SphK1 is elevated in many cancers. Here, we report that LPA markedly enhanced SphK1 mRNA and protein in gastric cancer MKN1 cells but had no effect on SphK2. LPA also up-regulated SphK1 expression in other human cancer cells that endogenously express the LPA₁ receptor, such as DLD1 colon cancer cells and MDA-MB-231 breast cancer cells, but not in HT29 colon cancer cells or MDA-MB-453 breast cancer cells, which do not express the LPA₁ receptor. An LPA₁ receptor antagonist or down-regulation of its expression prevented SphK1 and S1P₃ receptor up-regulation by LPA. LPA transactivated the epidermal growth factor receptor (EGFR) in these cells, and the EGFR inhibitor AG1478 attenuated the increased SphK1 and S1P₃ expression induced by LPA. Moreover, down-regulation of SphK1 attenuated LPA-stimulated migration and invasion of MNK1 cells yet had no effect on expression of neovascularizing factors, such as interleukin (IL)-8, IL-6, urokinase-type plasminogen activator (uPA), or uPA receptor induced by LPA. Finally, down-regulation of S1P₃, but not S1P₁, also reduced LPA-stimulated migration and invasion of MKN1 cells. Collectively, our results suggest that SphK1 is a convergence point of multiple cell surface receptors for three different ligands, LPA, EGF, and S1P, which have all been implicated in regulation of motility and invasiveness of cancer cells. [Cancer Res 2008;68(16):6569–77]

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				M. Maceyka, S. Milstien, and S. Spiegel Sphingosine-1-phosphate: the Swiss army knife of sphingolipid signaling J. Lipid Res., April 1, 2009; 50(Supplement): S272 - S276. [Abstract] [Full Text] [PDF]