Sphingosine Kinases and Sphingosine-1-Phosphate are Critical for TGF-Induced ERK1/2 Activation and Promotion of Migration and Invasion of Esophageal Cancer Cells

Departments of Microbiology and Immunology, and Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA

^* To whom correspondence should be addressed. Email: dlebman{at}vcu.edu.

	Abstract

TGF plays a dual role in oncogenesis acting as both a tumor suppressor and a tumor promoter. These disparate processes are mediated primarily by Smad and non-Smad signaling, respectively. A central issue in understanding the role of TGF in the progression of epithelial cancers is elucidation of the mechanisms underlying activation of non-Smad signaling cascades. Because the potent lipid mediator sphingosine-1-phosphate has been shown to transactivate the TGF receptor and activate Smad3, we examined its role in TGF activation of ERK1/2 and promotion of migration and invasion of esophageal cancer cells. Both S1P and TGF activate ERK1/2, but only TGF activates Smad3. Both ligands promoted ERK1/2-dependent migration and invasion. Furthermore, TGF rapidly increased S1P, which was required for TGF induced ERK1/2 activation as well as migration and invasion since downregulation of sphingosine kinases, the enzymes that produce S1P, inhibited these responses. Finally, our data demonstrate that TGF activation of ERK1/2 as well as induction of migration and invasion is mediated at least in part by ligation of the S1P receptor, S1P₂. Thus, these studies provide the first evidence that TGF activation of sphingosine kinases and formation of S1P contribute to non-Smad signaling and could be important for progression of esophageal cancer.