Desbois-Mouthon Christèle, Cacheux Wulfran, Blivet-Van Eggelpoël Marie-José, Barbu Véronique, Fartoux Laetitia, Poupon Raoul, Housset Chantal, Rosmorduc Olivier
Institut National de la Recherche Médicale INSERM, Unit 680, F-75012 Paris, France.
Int J Cancer. 2006 Dec 1;119(11):2557-66. doi: 10.1002/ijc.22221.
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.
表皮生长因子受体（EGFR）和1型胰岛素样生长因子受体（IGF-1R）依赖性通路在肝细胞癌（HCC）中上调，并且在其他系统中已描述了这两种通路之间的相互作用。吉非替尼是一种特异性EGFR抑制剂，已显示可显著减少（尽管不是完全减少）大鼠肝硬化肝脏中的HCC形成。在此，我们研究了IGF-1R依赖性通路是否可能干扰肝癌细胞中的EGFR信号传导，如果是这样，这种相互作用是否可能影响吉非替尼在这些细胞中的抗肿瘤作用。我们表明，IGF2在HepG2和Hep3B细胞中的增殖作用需要通过双调蛋白的自分泌/旁分泌释放来激活EGFR。因此，针对EGFR或双调蛋白的中和抗体以及TAPI-1（一种肿瘤坏死因子-α转换酶的药理学抑制剂，双调蛋白的一种裂解酶）可抑制IGF2诱导的细胞外信号调节激酶活性和DNA合成。相应地，吉非替尼强烈抑制IGF2和EGF对细胞增殖的刺激作用。然而，虽然吉非替尼可阻断EGF对Akt的激活，但对IGF2激活Akt没有影响，并且其自身不会引起细胞凋亡。AG1024是一种选择性IGF-1R抑制剂，可诱导细胞凋亡，并且这种作用可被吉非替尼增强。总之，我们表明在HCC细胞中，IGF2/IGF-1R激活分别通过EGFR依赖性和非依赖性机制触发增殖和存活信号。IGF2/IGF-1R存活通路可能导致这些细胞对吉非替尼耐药。因此，抑制IGF2/IGF-1R信号传导可增强吉非替尼在HCC中的抗肿瘤作用。
