GSK-3β reactivation with LY294002 sensitizes hepatoma ells to chemotherapy-induced apoptosis

Eléonore Beurel, Michel Kornprobst, Marie José Blivet-Van Eggelpoël, Axelle Cadoret, Jacqueline Capeau, Christele Desbois-Mouthon

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Constitutive activation of phosphatidylinositol 3- kinase (PI3K) confers resistance to apoptotic stimuli induced by chemotherapeutic agents in a variety of cancer cells. Therefore, the comprehension of mechanisms whereby PI3K downregulation interferes with chemotherapy is of major clinical interest for the elaboration of combined anticancer treatment modalities. Here, we examined the molecular. mechanisms whereby the PI3K inhibitor LY294002 sensitized p53- and Fas-deficient hepatoma cells to etoposide and camptothecin. LY294002 increased Hep3B cell susceptibility to chemotherapy-induced apoptosis by enhancing the expression of DR4 and DR5 and the activation of caspase-8 and -3. Moreover, LY294002-mediated sensitization to chemotherapy involved mitochondrial Bax translocation and cytosolic cytochrome c accumulation. In Hep3B cells, LY294002 led to the reactivation of glycogen synthase kinase-3β (GSK-36) by promoting its dephosphorylation on the serine 9 residue independently from Akt inhibition. The transient transfection of a constitutively active and nonphosphorylable S9AGSK-3β mutant sensitized cells to etoposide cytotoxic effects while cell treatment with the small GSK-3β inhibitor SB-415286 repressed the sensitizing effect of LY294002 on chemotherapy-induced apoptosis and caspase-8 activation. Altogether, our results show that LY294002 sensitizes hepatoma cells to chemotherapy-induced apoptosis via death receptor and mitochondria signalling pathways and that GSK-3β reactivation is involved in this process. Therefore, PI3K-mediated GSK-3B inhibition could be a mechanism by which cancer cells escape from chemotherapy- induced apoptosis.

Original languageEnglish (US)
Pages (from-to)215-222
Number of pages8
JournalInternational journal of oncology
Volume27
Issue number1
StatePublished - Jul 1 2005
Externally publishedYes

Keywords

  • Camptothecin
  • Death receptor
  • Etoposide
  • Mitochondria
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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