GSK-3beta inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression.
Lithium exerts neuroprotective actions that involve the inhibition of glycogen synthase kinase-3beta (GSK-3beta). Otherwise, recent studies suggest that sustained GSK-3beta inhibition is a hallmark of tumorigenesis. In this context, the present study was undertaken to examine whether lithium modulated cancer cell sensitivity to apoptosis induced by chemotherapy agents. We observed that, in different human cancer cell lines, lithium significantly reduced etoposide- and camptothecin-induced apoptosis. In HepG2 cells, lithium repressed drug induction of CD95 expression and clustering at the cell surface as well as caspase-8 activation. Lithium acted through deregulation of GSK-3beta signaling since (1) it provoked a rapid and sustained phosphorylation of GSK-3beta on the inhibitory serine 9 residue; (2) the GSK-3beta inhibitor SB-415286 mimicked lithium effects by repressing drug-induced apoptosis and CD95 membrane expression; and (3) lithium promoted the disruption of nuclear GSK-3beta/p53 complexes. Moreover, the overexpression of an inactivated GSK-3beta mutant counteracted the stimulatory effects of etoposide and camptothecin on a luciferase reporter plasmid driven by a p53-responsive sequence from the CD95 gene. In conclusion, we provide the first evidence that lithium confers resistance to apoptosis in cancer cells through GSK-3beta inhibition and subsequent repression of CD95 gene expression. Our study also highlights the concerted action of GSK-3beta and p53 on CD95 gene expression.
INSERM U.402, Faculté de Médecine Saint-Antoine, Paris, France.
Eléonore
E
Beurel
Michel
M
Kornprobst
Marie-José
MJ
Blivet-Van Eggelpoël
Carmen
C
Ruiz-Ruiz
Axelle
A
Cadoret
Jacqueline
J
Capeau
Christèle
C
Desbois-Mouthon
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002166:Camptothecin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics*
D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D005047:Etoposide; D008094:Lithium; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D002166:Camptothecin