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Impact of IGF‐1R/EGFR cross‐talks on hepatoma cell sensitivity to gefitinib
Author(s) -
DesboisMouthon Christèle,
Cacheux Wulfran,
BlivetVan Eggelpoël MarieJosé,
Barbu Véronique,
Fartoux Laetitia,
Poupon Raoul,
Housset Chantal,
Rosmorduc Olivier
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22221
Subject(s) - gefitinib , amphiregulin , autocrine signalling , epidermal growth factor receptor , cancer research , paracrine signalling , egfr inhibitors , juxtacrine signalling , epidermal growth factor , protein kinase b , signal transduction , growth factor , growth factor receptor , biology , chemistry , medicine , receptor , microbiology and biotechnology
Epidermal growth factor receptor (EGFR)‐ and type 1 insulin‐like growth factor receptor (IGF‐1R)‐dependent pathways are up‐regulated in hepatocellular carcinoma (HCC), and cross‐talks between both pathways have been described in other systems. Gefitinib, a specific EGFR inhibitor, has shown to reduce significantly, although not completely, HCC formation in rat cirrhotic liver. Here, we investigated whether IGF‐1R‐dependent pathways may interfere with EGFR signalling in hepatoma cells and, if so, whether such cross‐talks may affect the antitumoral effect of gefitinib in these cells. We show that the proliferative action of IGF2 in HepG2 and Hep3B cells requires EGFR activation through the autocrine/paracrine release of amphiregulin. Thus, IGF2‐induced extracellular signal‐regulated kinase activity and DNA synthesis were inhibited by neutralizing antibodies against either EGFR or amphiregulin and by TAPI‐1, a pharmalogical inhibitor of tumor necrosis factor‐α converting enzyme, a sheddase of amphiregulin. Accordingly, IGF2 and EGF stimulating effects on cell proliferation were both strongly repressed by gefitinib. However, while gefitinib blocked Akt activation by EGF, it had no effect on Akt activation by IGF2 and did not cause apoptosis by its own. AG1024, a selective IGF‐1R inhibitor, induced apoptosis and this effect was potentiated by gefitinib. In conclusion, we show that in HCC cells IGF2/IGF‐1R activation triggers proliferative and survival signals through EGFR‐dependent and ‐independent mechanisms, respectively. The IGF2/IGF‐1R survival pathway may contribute to gefitinib resistance in these cells. Therefore, the inhibition of IGF2/IGF‐1R signalling could potentiate the anti‐tumoral effect of gefinitib in HCC. © 2006 Wiley‐Liss, Inc.