lithium-chloride and Kidney-Neoplasms

Inappropriate activation of the Wnt/APC/beta-catenin signaling pathways plays a critical role at early stages in a variety of human cancers. However, their respective implication in tumor cell invasion is still hypothetical. Here, we show that two activators of the canonical Wnt/beta-catenin transcription pathway, namely Dvl-2, the Axin 501-560 fragment binding glycogen synthase kinase -3beta (GSK-3beta), and the negative Wnt regulator wt-Axin did not alter cell invasion into type I collagen. In addition, both Dvl-2 and Axin 501-560 exerted a permissive action on the proinvasive activity of HGF and intestinal trefoil factor. Upstream activation of Wnt signaling by the Wnt-2 and Wnt-3a ligands, stable overexpression of Wnt-2, as well as GSK-3beta inhibition by lithium, SB216763, and GSK-3beta dominant negative forms (K85R and R96E) conferred the invasive phenotype through several proinvasive pathways. Induction of the matrix metalloprotease MMP-7 (matrilysin) gene and protein by Wnt-2 was abolished by inactivation of the AP-1 binding site in the promoter. Accordingly, invasion induced by Wnt-2 was prevented by soluble FRP-3 and FRP-1, sequestration of Gbetagamma subunits, depletion of the GSK-3beta protein by RNA interference, the c-Jun dominant negative mutant TAM67 and was not reversed by wt-Axin. Thus, the proinvasive activity of Wnt-2 is mediated by a noncanonical Wnt pathway using GSK-3beta and the AP-1 oncogene. Our data provide a potential clue for our understanding of the action and crosstalk between Wnt activators and other proinvasive pathways, in relation with matrix substrates and proteases in human cancers.

Topics: Animals; Antibodies, Monoclonal; Axin Protein; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Colonic Neoplasms; Colorectal Neoplasms; Dogs; Epithelial Cells; Genetic Vectors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Glycoproteins; Heterotrimeric GTP-Binding Proteins; HT29 Cells; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Neoplasms; Ligands; Lithium Chloride; Maleimides; Matrix Metalloproteinase 7; Neoplasm Invasiveness; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-jun; Repressor Proteins; Retroviridae; Signal Transduction; Transcription Factor AP-1; Transcription, Genetic; Wnt Proteins; Wnt2 Protein