lithium-chloride and Cell-Transformation--Viral

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.

Topics: Animals; Blotting, Western; Cell Movement; Cell Proliferation; Cell Transformation, Viral; Chick Embryo; Chorioallantoic Membrane; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Glutathione; Lithium Chloride; Lithium Compounds; Matrix Metalloproteinase 2; Mice; Microscopy, Fluorescence; Neoplasms, Experimental; NIH 3T3 Cells; Okadaic Acid; Oncogene Protein pp60(v-src); Phosphorylation; Protein Tyrosine Phosphatases; Reactive Oxygen Species; Vanadates

The metabolism of phosphatidylinositol (PtdIns) was studied in a mink lung epithelial cell line and its subclones transformed by feline sarcoma viruses containing either the v-fms or v-fes oncogenes. The transformed cell lines had a higher rate of PtdIns turnover but did not have elevated levels of phosphorylated PtdIns species or PtdIns kinase activity. Significantly higher specific activities of a guanine nucleotide-activated PtdIns-4,5-diphosphate phospholipase C were detected in both transformed cell lines (F3CL7(v-fes), 55 pmol/min/mg of protein and G2M(v-fms), 18 pmol/min/mg of protein) as compared to the nontransformed parental cell line (CCL64, 2 pmol/min/mg of protein). The guanine nucleotide-stimulated phospholipase C activity was specific for PtdIns-4,5-diphosphate, and the water-soluble hydrolysis product was inositol 1,4,5-triphosphate. Both GTP and nonhydrolyzable GTP analogs activated the phospholipase C, whereas ATP was weakly effective and GDP was inactive. The phospholipase C activity was maximally active in the presence of 9 mM sodium cholate, had a sharp pH optimum of pH 6.5, and was not activated by calcium although hydrolysis was inhibited by high concentrations of EDTA. These data point to enhanced production of diacylglycerol and inositol 1,4,5-triphosphate second messengers in transformed cells due to the activation of guanine nucleotide-dependent PtdIns-4,5-diphosphate-specific phospholipase C and suggest that the generation of aberrant hormonally independent signals is associated with cell transformation by oncogenes encoding tyrosine-specific protein kinases.

Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Calcium; Cell Line; Cell Membrane; Cell Transformation, Neoplastic; Cell Transformation, Viral; Chlorides; Epithelium; Guanine Nucleotides; Inositol; Kinetics; Lithium; Lithium Chloride; Lung; Mink; Oncogenes; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphotransferases; Retroviridae; Sarcoma Viruses, Feline; Type C Phospholipases