Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib.
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-alpha 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.
Desbois-Mouthon
Christèle
C
Institut National de la Recherche Médicale INSERM, Unit 680, F-75012 Paris, France.
Cacheux
Wulfran
W
Blivet-Van Eggelpoël
Marie-José
MJ
Barbu
Véronique
V
Fartoux
Laetitia
L
Poupon
Raoul
R
Housset
Chantal
C
Rosmorduc
Olivier
O
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D020239:Receptor Cross-Talk; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D000970:Antineoplastic Agents; D011799:Quinazolines; D007335:Insulin-Like Growth Factor II; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000077156:Gefitinib