Sphingosine kinases and sphingosine-1-phosphate are critical for TGF-b- induced ERK1/2 activation and promotion of migration and invasion of esophageal cancer cells.

MILLER AV; ALVAREZ SE; SPIEGEL S; LEBMAN DA

MOLECULAR AND CELLULAR BIOLOGY

AMER SOC MICROBIOLOGY

Año: 2008 vol. 28 p. 4142 - 4151

0270-7306

Transforming growth factor b(TGF-b) plays a dual role in oncogenesis, acting as both a tumor suppressor and a tumor promoter. These disparate processes of suppression and promotion are mediated primarily by Smad and non-Smad signaling, respectively. A central issue in understanding the role of TGF b in the progression of epithelial cancers is the elucidation of the mechanisms underlying activation of non-Smad signaling cascades. Because the potent lipid mediator sphingosine-1-phosphate (S1P) has been shown to transactivate the TGF receptor and activate Smad3, we examined its role in TGF activation of extracellular signal-regulated kinases 1 and 2 (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, S1PR2. Thus, these studies provide the first evidence that TGF activation of sphingosine kinasesand formation of S1P contribute to non-Smad signaling and could be important for progression of esophageal cancer.