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Lithium inhibits the cytolytic glucocorticoid effect on S49 mouse lymphoma cells
Abstract:
Cytolysis is the end point of receptor-mediated effects of glucocorticoids on S49 mouse lymphoma cells of wild-type. In the presence of 5 mM LiCl this effect of triamcinolone or dexamethasone was markedly delayed. The cytoprotective effect of Li+ against 10(-7) M triamcinolone acetonide was already manifest after 24 h of steroid incubation, and on the fifth day 50-fold more Li+-treated than control cells were viable. This effect of Li+ was not exerted through changes of the doubling time of the cells, and thus could not be ascribed to an overall reduction of protein- or RNA synthesis. Data on accumulation and effect of cyclic AMP indicated that the cytoprotective effect was independent on cyclic AMP. Furthermore Li+ did not affect the amount or affinity of glucocorticoid receptors in intact cells. By use of aqueous 2-phase partitioning and DNA-Sepharose binding of [3H]triamcinolone acetonide labelled cytosols we demonstrate that Li+ inhibits the in vitro salt-activation of the glucocorticoid-receptor complexes by 60-100%. The nuclear bound fraction of hormone-receptor complexes in intact cells at 37 degrees C was not affected by Li+. The data suggest that Li+ inhibits the cytolytic glucocorticoid effect by interacting with the hormone-receptor complexes.
Insights
Lithium chloride (LiCl) protects S49 mouse lymphoma cells from glucocorticoid-induced cytolysis. Li+ delays steroid effects by inhibiting glucocorticoid-receptor complex salt-activation, not by altering cell growth or receptor binding.
Area of Science:
- Cell Biology
- Molecular Pharmacology
Background:
- Glucocorticoids induce cytolysis in S49 mouse lymphoma cells via receptor-mediated pathways.
- Understanding the mechanisms of glucocorticoid action and resistance is crucial in cancer therapy.
Purpose of the Study:
- To investigate the cytoprotective effect of lithium chloride (LiCl) against glucocorticoid-induced cell death.
- To elucidate the molecular mechanisms underlying LiCl's protective action.
Main Methods:
- Treatment of S49 mouse lymphoma cells with glucocorticoids (triamcinolone, dexamethasone) and LiCl.
- Cell viability assays, cell doubling time measurements, protein and RNA synthesis analysis.
- Cyclic AMP accumulation assays.
- Glucocorticoid receptor binding assays.
- In vitro salt-activation assays using aqueous 2-phase partitioning and DNA-Sepharose binding.
Main Results:
- LiCl significantly delayed glucocorticoid-induced cytolysis, with 50-fold more viable cells after 5 days of treatment.
- LiCl's protective effect was independent of changes in cell doubling time, protein synthesis, RNA synthesis, or cyclic AMP levels.
- Li+ did not alter the amount or affinity of glucocorticoid receptors in intact cells.
- LiCl inhibited the in vitro salt-activation of glucocorticoid-receptor complexes by 60-100%.
- Nuclear-bound hormone-receptor complexes in intact cells were unaffected by Li+.
Conclusions:
- LiCl exerts a potent cytoprotective effect against glucocorticoids in S49 cells.
- The mechanism involves Li+ interacting with and inhibiting the salt-activation of glucocorticoid-receptor complexes.
- This interaction occurs post-receptor binding and does not affect nuclear translocation.