Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor
Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor
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DOI：
10.1074/jbc.m108863200
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发表时间：
2002-08-02
影响因子：
4.8
通讯作者：
Streuli, CH
中科院分区：
文献类型：
--
作者：
Gilmore, AP;Valentijn, AJ;Streuli, CH
新的癌症化疗药物需要通过激活促凋亡蛋白来诱导细胞凋亡。表皮生长因子(EGF)和胰岛素样生长因子(IGF)在许多上皮细胞中都能提供强有力的生存刺激，其受体的激活在实体人类肿瘤中也很常见。在这里，我们证明了在癌症的第三阶段临床试验中，一种新药ZD1839阻断EGF受体，可以有效地诱导乳腺上皮细胞株和原代培养细胞的凋亡，以及乳腺癌患者的原发胸腔积液。我们确定了ZD1839诱导细胞凋亡的机制。我们证明，它通过激活促凋亡蛋白BAD来阻止细胞存活。此外，我们证明了IGF反式激活EGF受体，并且ZD1839阻断了IGF介导的MAPK和BAD的磷酸化。许多癌症治疗方法通过靶向DNA而诱导细胞凋亡来杀死肿瘤细胞；然而，通过DNA损伤触发细胞凋亡的阈值往往与正常细胞不同。我们的结果表明，通过靶向生长因子介导的生存信号通路，BAD的磷酸化可以在治疗上被操纵以诱导细胞凋亡。
Novel cancer chemotherapeutics are required to induce apoptosis by activating pro-apoptotic proteins. Both epidermal growth factor (EGF) and insulin-like growth factor (IGF) provide potent survival stimuli in many epithelia, and activation of their receptors is commonly observed in solid human tumors. Here we demonstrate that blockade of the EGF receptor by a new drug in phase III clinical trails for cancer, ZD1839, potently induces apoptosis in mammary epithelial cell lines and primary cultures, as well as in a primary pleural effusion from a breast cancer patient. We identified the mechanism of apoptosis induction by ZD1839. We showed that it prevents cell survival by activating the pro-apoptotic protein BAD. Moreover, we demonstrate that IGF transactivates the EGF receptor and that ZD1839 blocks IGF-mediated phosphorylation of MAPK and BAD. Many cancer therapies kill tumor cells by inducing apoptosis as a consequence of targeting DNA; however, the threshold at which apoptosis can be triggered through DNA damage is often different from that in normal cells. Our results indicate that by targeting a growth factor-mediated survival signaling pathway, BAD phosphorylation can be manipulated therapeutically to induce apoptosis.