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Pleiotropic Effects of PI‐3′ Kinase/Akt Signaling in Human Hepatoma Cell Proliferation and Drug‐Induced Apoptosis
Author(s) -
ALEXIA CATHERINE,
BRAS MARLÈNE,
FALLOT GUILLAUME,
VADROT NATHALIE,
DANIEL FANNY,
LASFER MALIKA,
TAMOUZA HOUDA,
GROYER ANDRÉ
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1378.001
Subject(s) - protein kinase b , apoptosis , signal transduction , microbiology and biotechnology , cancer research , chemistry , pi3k/akt/mtor pathway , doxorubicin , phosphorylation , cell growth , biology , biochemistry , genetics , chemotherapy
IGF‐II and type I‐IGF receptor (IGF‐IR) gene expression is increased in primary liver tumors, and transgenic mice overexpressing IGF‐II in the liver develop hepatocellular carcinoma (HCC) spontaneously, suggesting that alterations of IGF‐IR signaling in vivo may play a role in the auto/paracrine control of hepatocarcinogenesis. We have addressed the contribution of PI‐3′K/Akt signaling on the proliferation of HepG 2 human hepatoma cells and on their protection against doxorubicin‐induced apoptosis. Both basal HepG 2 cell DNA replication and that stimulated by IGF‐IR signaling were inhibited by the specific PI‐3′K inhibitor Ly294002 (Ly). In the former case, PI‐3′K signaling overcame cell cycle arrest in G 1 via increased cyclin D 1 protein and decreased p27 kip1 gene expression. Doxorubicin treatment induced apoptosis in HepG 2 cells and was concomitant with the proteolytic cleavage of Akt‐1 and ‐2. Drug‐induced apoptosis was reversed by IGF‐I and this effect was (i) dependent on Akt‐1 and ‐2 phosphorylation and (ii) accompanied by the inhibition of initiator caspase‐9 activity, suggesting that IGF‐IR signaling interferes with mitochondria‐dependent apoptosis. Accordingly, Ly enhanced doxorubicin‐induced apoptosis and suppressed its reversal by IGF‐I. Altogether, the data emphasize the crucial role of PI‐3′K/Akt signaling (i) in basal as well as IGF‐IR‐stimulated HepG 2 cell proliferation and (ii) in controlling both doxorubicin‐induced apoptosis (e.g., drug‐induced cleavage of Akt) and its reversal by IGF‐I (protection against apoptosis parallels the extent of Akt phosphorylation). They suggest that targeting Akt activity or downstream Akt effectors (e.g., GSK3‐beta, FOXO transcription factors) may help define novel therapeutic strategies of increased efficacy in the treatment of HCC‐bearing patients.