Visit our Expo - Redox and Inflammation signaling 2012

Session III : Protein kinase cascades as therapeutic targets Poster III, 2
Multiple roles of PI-3’ kinase / Akt signaling in human hepatoma cell proliferation and
drug-induced apoptosis
Catherine alexia 3, Marlène Bras 2, Guillaume Fallot 3, Nathalie Vadrot 3, Fanny
Daniel 3, Malika Lasfer 3, Houda Tamouza 3 & André Groyer 1
1 Inserm U.683 and 3 Inserm U.481, Faculté de Médecine Xavier Bichat, 75870 Paris
Cédex 18, France ; 2 Institut Pasteur, Département d'Immunologie, 75724 Paris Cedex
15, France. e-mail: groyer@bichat.inserm.fr
IGF-II and type I-IGF receptor (IGF-IR) gene expression is increased in primary liver
tumours and transgenic mice over-expressing IGF-II in the liver develop hepatocarcinoma
(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 HepG2 human hepatoma cells and on their
protection against doxorubicin-induced apoptosis. Both basal HepG2 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 G1 via
increased cyclin D1 protein and decreased p130Rb and p27kip1 gene expression. Doxorubicin
treatment induced apoptosis in HepG2 cells and was concomitant with the proteolytic
cleavage of Akt-1 and -2. Drug-induced apoptosis was reversed by IGF-I and 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 HepG2 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.
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