Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells

Eleonore Beurel, Marie José Blivet-Van Eggelpoël, Michel Kornprobst, Sylviane Moritz, Roland Delelo, François Paye, Chantal Housset, Christèle Desbois-Mouthon

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) displays a striking resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Therefore, the characterization of pharmacological agents that overcome this resistance may provide new therapeutic modalities for HCC. Here, we examined whether glycogen synthase kinase-3 (GSK-3) inhibitors could restore TRAIL sensitivity in hepatoma cells. To this aim, the effects of two GSK-3 inhibitors, lithium and SB-415286, were analyzed on TRAIL apoptotic signaling in human hepatoma cell lines in comparison with normal hepatocytes. We observed that both inhibitors sensitized hepatoma cells, but not normal hepatocytes, to TRAIL-induced apoptosis by enhancing caspase-8 activity and the downstream recruitment of the mitochondrial machinery. GSK-3 inhibitors also stabilized p53 and the down-regulation of p53 by RNA interference abolished the sensitizing effect of lithium on caspase-3 activation. Concomitantly, GSK-3 inhibitors strongly activated c-Jun N-terminal kinases (JNKs). The pharmacological inhibition of JNKs with AS601245 or SP600125 resulted in an earlier and stronger induction of apoptosis indicating that activated JNKs transduced protective signals and provided an anti-apoptotic balance to the pro-apoptotic effects of GSK-3 inhibitors. These findings demonstrate that GSK-3 exerts a negative and complex constraint on TRAIL apoptotic signaling in hepatoma cells, which can be greatly alleviated by GSK-3 inhibitors. Therefore, GSK-3 inhibitors may open new perspectives to enhance the anti-tumor activity of TRAIL in HCC.

Original languageEnglish
Pages (from-to)54-65
Number of pages12
JournalBiochemical Pharmacology
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

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Glycogen Synthase Kinase 3
Hepatocellular Carcinoma
Apoptosis
Lithium
Hepatocytes
Phosphotransferases
Personnel Selection
Pharmacology
Caspase 8
JNK Mitogen-Activated Protein Kinases
RNA Interference
Caspase 3
Machinery
Tumors
Down-Regulation
Tumor Necrosis Factor-alpha
Chemical activation
Cells
RNA
Ligands

Keywords

  • Apoptosis
  • c-Jun N-terminal kinase
  • CD95
  • Hepatocellular carcinoma
  • Lithium
  • SB-415286

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Beurel, E., Blivet-Van Eggelpoël, M. J., Kornprobst, M., Moritz, S., Delelo, R., Paye, F., ... Desbois-Mouthon, C. (2009). Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. Biochemical Pharmacology, 77(1), 54-65. https://doi.org/10.1016/j.bcp.2008.09.026

Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. / Beurel, Eleonore; Blivet-Van Eggelpoël, Marie José; Kornprobst, Michel; Moritz, Sylviane; Delelo, Roland; Paye, François; Housset, Chantal; Desbois-Mouthon, Christèle.

In: Biochemical Pharmacology, Vol. 77, No. 1, 01.01.2009, p. 54-65.

Research output: Contribution to journalArticle

Beurel, E, Blivet-Van Eggelpoël, MJ, Kornprobst, M, Moritz, S, Delelo, R, Paye, F, Housset, C & Desbois-Mouthon, C 2009, 'Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells', Biochemical Pharmacology, vol. 77, no. 1, pp. 54-65. https://doi.org/10.1016/j.bcp.2008.09.026
Beurel, Eleonore ; Blivet-Van Eggelpoël, Marie José ; Kornprobst, Michel ; Moritz, Sylviane ; Delelo, Roland ; Paye, François ; Housset, Chantal ; Desbois-Mouthon, Christèle. / Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. In: Biochemical Pharmacology. 2009 ; Vol. 77, No. 1. pp. 54-65.
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