Lithium suppresses motility and invasivity of v-src-transformed cells by glutathione-dependent activation of phosphotyrosine phosphatases.
Lithium has long been used for the treatment and prophylaxis of bipolar mood disorder. However, nerve cells are not the sole targets of lithium. Indeed, lithium was reported to target numerous cell types, and affect cell proliferation, differentiation and death. Thus, the idea has been raised that lithium may act on signaling pathways involved in neoplastic transformation. Indeed, the effect of lithium on tumor progression is currently being tested in a limited number of clinical trials. However, the molecular mechanisms by which lithium affects neoplastic transformation remain to be characterized. Here, using mouse fibroblasts transformed by the v-src oncogene as a model, we show that lithium drastically inhibits cell motility and compromises the invasive phenotype of v-src-transformed cells. In addition, we show that this effect is mediated by the activation of phosphotyrosine phosphatases, but not by the direct inhibition of the v-Src tyrosine kinase. Finally, we show that lithium activates phosphotyrosine phosphatases by the modulation of the redox status of the cell, independently of the Wnt and the inositol phosphate canonical pathways. Thus, this study supports the idea that lithium, acting similar to an antioxydizer, may have antimetastatic properties in vivo.
Néel
B D
BD
Université de Lyon, Institut de Biologie et Chimie des Protéines UMR 5086 CNRS-Université Lyon I, IFR 128, 7, Lyon cedex 07, France.
Lopez
J
J
Chabadel
A
A
Gillet
G
G
D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002472:Cell Transformation, Viral; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D018020:Lithium Compounds / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000473:pathology; D019319:Okadaic Acid / Q000494:pharmacology; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018020:Lithium Compounds; D017382:Reactive Oxygen Species; D019319:Okadaic Acid; D014638:Vanadates; D015688:Oncogene Protein pp60(v-src); D017027:Protein Tyrosine Phosphatases; D020778:Matrix Metalloproteinase 2; D018021:Lithium Chloride; D005978:Glutathione