Role of Constitutively Activated and Insulin-Like Growth Factor-Stimulated ERK1/2 Signaling in Human Hepatoma Cell Proliferation and Apoptosis: Evidence for Heterogeneity of Tumor Cell Lines

• Published in: Annals of the New York Academy of Sciences 2004-12, Vol.1030 (1), p.219-229
• Main Authors: ALEXIA, CATHERINE, LASFER, MALIKA, GROYER, ANDRÉ
• Format: Article
• Language: English
• Subjects: apoptosis; Apoptosis - drug effects; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - pathology; Cell Division; Cell Line, Tumor; DNA Replication - drug effects; human hepatoma cell lines; Humans; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor II - pharmacology; insulin-like growth factors; Liver Neoplasms - enzymology; Liver Neoplasms - pathology; MAP kinase (ERK) signaling; Mitogen-Activated Protein Kinases - metabolism; proliferation; Signal Transduction - drug effects
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1196/annals.1329.028

: Enhanced insulin‐like growth factor II (IGF‐II) and type I IGF receptor (IGF‐IR) gene expression in liver tumors and the development of liver tumors in transgenic mice overexpressing IGF‐II in the liver suggest that the IGFs and underlying signaling cascades may play auto/paracrine roles in the control of hepatocarcinoma (HCC) cell proliferation and in their protection against apoptosis. We have focused on the role of mitogen‐activated protein kinase (ERK1/2) signaling on human HepG2 and Huh‐7 hepatoma cell proliferation and on the protection of these cells against drug‐induced apoptosis. Physiological concentrations of IGF‐I stimulated DNA replication in HepG2 cells (1.5‐fold) but not in Huh‐7 cells, and this effect was abolished by PD98059 (MEK‐1 inhibitor). Doxorubicin or cisplatin treatment induced apoptosis (caspase‐dependent poly[ADP‐ribose]polymerase cleavage) in both cell lines, but dose‐dependent reversion of drug‐induced apoptosis (57–84%) by IGF‐I was only observed in HepG2 cells. The very low level of IGF‐IR at the plasma membrane of Huh‐7 cells may account for their unresponsiveness to IGF‐I. We have shown that drug treatment enhanced (17‐fold) or did not modify constitutive ERK1/2 activity in cultured HepG2 or Huh‐7 cells, respectively. In both cell lines, inhibition of constitutive and drug‐induced ERK1/2 activity by PD98059 yielded a complete inhibition of drug‐induced apoptosis. Altogether, our data demonstrate the heterogeneous response of human hepatoma cells to an IGF stimulus and suggest (1) that auto/paracrine effects of IGF‐I/‐II might contribute to the proliferation of HCC cells and to their protection against apoptosis in vivo and (2) that drug‐induced activation of ERK1/2 plays a role in drug‐induced apoptosis in human hepatoma cells.