Crosstalk Between LPA1 and EGF Receptors Mediates Upregulation of Sphingosine Kinase 1 to Promote Gastric Cancer Cell Motility and Invasion.

SHIDA D; FANG X; KORDULA T; TAKABE K; LEPINE S; ALVAREZ SE; MILSTIEN S; SPIEGEL S

CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Año: 2008 p. 6569 - 6577

0008-5472

Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are lysophospholipid mediators of diverse cellular processes important for cancer progression. S1P is producedby 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 gastriccancer MKN1 cells but had no effect on SphK2. LPA also upregulated SphK1 expression in other human cancer cells that endogenously express the LPA1 receptor,such as DLD1 coloncancer 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) inthese cells,and the EGFR inhibitor AG1478 attenuated the increased SphK1 and S1P3 expression induced by LPA. Moreover, down-r egulation of SphK1 attenuated LPA-stimulatedmigration 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-r egulation 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.