安非雷古林
胰岛素样生长因子1受体
吉非替尼
表皮生长因子受体
癌症研究
酪氨酸激酶
生物
表皮生长因子
生长因子受体
受体酪氨酸激酶
生长因子
激酶
受体
信号转导
细胞生物学
生物化学
作者
Marie Guérard,Thomas Robin,Pascal Perron,Anne‐Sophie Hatat,Laurence David-Boudet,Laetitia Vanwonterghem,Benoît Busser,Jean‐Luc Coll,Sylvie Lantuéjoul,Béatrice Eymin,Amandine Hurbin,Sylvie Gazzéri
标识
DOI:10.1016/j.canlet.2018.01.080
摘要
Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xenografts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin-β1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer.
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