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Pleiotropic effects of PI-3' kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis.
Ann N Y Acad Sci. 2006 Dec; 1090:1-17.AN

Abstract

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 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 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 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 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.

Authors+Show Affiliations

INSERM U.481, Faculté de Médecine Xavier Bichat, 16, rue Henri Huchard, BP 416, 75870-Paris Cédex 18, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17384242

Citation

Alexia, Catherine, et al. "Pleiotropic Effects of PI-3' kinase/Akt Signaling in Human Hepatoma Cell Proliferation and Drug-induced Apoptosis." Annals of the New York Academy of Sciences, vol. 1090, 2006, pp. 1-17.
Alexia C, Bras M, Fallot G, et al. Pleiotropic effects of PI-3' kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis. Ann N Y Acad Sci. 2006;1090:1-17.
Alexia, C., Bras, M., Fallot, G., Vadrot, N., Daniel, F., Lasfer, M., Tamouza, H., & Groyer, A. (2006). Pleiotropic effects of PI-3' kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis. Annals of the New York Academy of Sciences, 1090, 1-17.
Alexia C, et al. Pleiotropic Effects of PI-3' kinase/Akt Signaling in Human Hepatoma Cell Proliferation and Drug-induced Apoptosis. Ann N Y Acad Sci. 2006;1090:1-17. PubMed PMID: 17384242.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pleiotropic effects of PI-3' kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis. AU - Alexia,Catherine, AU - Bras,Marlène, AU - Fallot,Guillaume, AU - Vadrot,Nathalie, AU - Daniel,Fanny, AU - Lasfer,Malika, AU - Tamouza,Houda, AU - Groyer,André, PY - 2007/3/27/pubmed PY - 2007/4/27/medline PY - 2007/3/27/entrez SP - 1 EP - 17 JF - Annals of the New York Academy of Sciences JO - Ann N Y Acad Sci VL - 1090 N2 - 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 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 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 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 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. SN - 0077-8923 UR - https://www.unboundmedicine.com/medline/citation/17384242/Pleiotropic_effects_of_PI_3'_kinase/Akt_signaling_in_human_hepatoma_cell_proliferation_and_drug_induced_apoptosis_ DB - PRIME DP - Unbound Medicine ER -