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首页> 外文期刊>EMBO reports >Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation
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Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation

机译：ERRFI1在EGFR和AKT途径调节中的差异作用影响癌症增殖

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AKT signaling is modulated by a complex network of regulatory proteins and is commonly deregulated in cancer. Here, we present a dual mechanism of AKT regulation by the ERBB receptor feedback inhibitor 1 (ERRFI1). We show that in cells expressing high levels of EGFR, ERRF1 inhibits growth and enhances responses to chemotherapy. This is mediated in part through the negative regulation of AKT signaling by direct ERRFI1-dependent inhibition of EGFR. In cells expressing low levels of EGFR, ERRFI1 positively modulates AKT signaling by interfering with the interaction of the inactivating phosphatase PHLPP with AKT, thereby promoting cell growth and chemotherapy desensitization. These observations broaden our understanding of chemotherapy response and have important implications for the selection of targeted therapies in a cell context-dependent manner. EGFR inhibition can only sensitize EGFR-high cells for chemotherapy, while AKT inhibition increases chemosensitivity in EGFR-low cells. By understanding these mechanisms, we can take advantage of the cellular context to individualize antineoplastic therapy. Finally, our data also suggest targeting of EFFRI1 in EGFR-low cancer as a promising therapeutic approach.
机译：Akt信号传导由调控蛋白的复杂网络调节，并且通常在癌症中造成危险。这里，我们介绍了ERBB受体反馈抑制剂1（ERRFI1）的AKT调节的双重机制。我们表明，在表达高水平EGFR的细胞中，ERRF1抑制生长并增强对化疗的反应。通过直接Erfi1依赖性抑制EGFR，部分通过AKT信号传导的负调节介导。在表达低水平的EGFR水平的细胞中，通过干扰灭活磷酸酶PHLPP与AKT的相互作用来肯定地调节AKT信号传导，从而促进细胞生长和化疗脱敏。这些观察结果拓宽了我们对化疗反应的理解，并对以细胞背景相关的方式选择有针对性疗法的重要意义。 EGFR抑制只能敏化EGFR高细胞进行化学疗法，而AKT抑制则增加EGFR-低细胞中的化学敏感性。通过了解这些机制，我们可以利用细胞背景来个体化抗肿瘤治疗。最后，我们的数据还表明Exfri1在Egfr-Low癌症中的靶向作为有希望的治疗方法。

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