GSK-3β inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression

Eleonore Beurel, Michel Kornprobst, Marie José Blivet-Van Eggelpoël, Carmen Ruiz-Ruiz, Axelle Cadoret, Jacqueline Capeau, Christèle Desbois-Mouthon

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Lithium exerts neuroprotective actions that involve the inhibition of glycogen synthase kinase-3β (GSK-3β). Otherwise, recent studies suggest that sustained GSK-3β 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-3β signaling since (1) it provoked a rapid and sustained phosphorylation of GSK-3β on the inhibitory serine 9 residue; (2) the GSK-3β inhibitor SB-415286 mimicked lithium effects by repressing drug-induced apoptosis and CD95 membrane expression; and (3) lithium promoted the disruption of nuclear GSK-3β/p53 complexes. Moreover, the overexpression of an inactivated GSK-3β 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-3β inhibition and subsequent repression of CD95 gene expression. Our study also highlights the concerted action of GSK-3β and p53 on CD95 gene expression.

Original languageEnglish
Pages (from-to)354-364
Number of pages11
JournalExperimental Cell Research
Volume300
Issue number2
DOIs
StatePublished - Nov 1 2004
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Lithium
Apoptosis
Drug Therapy
Camptothecin
Etoposide
Gene Expression
Neoplasms
Caspase 8
Hep G2 Cells
Luciferases
Pharmaceutical Preparations
Serine
Cluster Analysis
Carcinogenesis
Plasmids
Phosphorylation
Cell Line

Keywords

  • Apoptosis
  • Caspase-8
  • CD95
  • Chemotherapy
  • GSK-3β
  • Lithium
  • p53

ASJC Scopus subject areas

  • Cell Biology

Cite this

GSK-3β inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression. / Beurel, Eleonore; Kornprobst, Michel; Blivet-Van Eggelpoël, Marie José; Ruiz-Ruiz, Carmen; Cadoret, Axelle; Capeau, Jacqueline; Desbois-Mouthon, Christèle.

In: Experimental Cell Research, Vol. 300, No. 2, 01.11.2004, p. 354-364.

Research output: Contribution to journalArticle

Beurel, E, Kornprobst, M, Blivet-Van Eggelpoël, MJ, Ruiz-Ruiz, C, Cadoret, A, Capeau, J & Desbois-Mouthon, C 2004, 'GSK-3β inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression', Experimental Cell Research, vol. 300, no. 2, pp. 354-364. https://doi.org/10.1016/j.yexcr.2004.08.001
Beurel, Eleonore ; Kornprobst, Michel ; Blivet-Van Eggelpoël, Marie José ; Ruiz-Ruiz, Carmen ; Cadoret, Axelle ; Capeau, Jacqueline ; Desbois-Mouthon, Christèle. / GSK-3β inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression. In: Experimental Cell Research. 2004 ; Vol. 300, No. 2. pp. 354-364.
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