阿法替尼通过PERK-eIF2α-ATF4轴下调MCL-1表达，导致头颈部鳞状细胞癌细胞凋亡

2016年8月，山东大学附属山东省医院耳鼻咽喉头颈外科，山东省耳科重点实验室(Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, P. R. China；Shandong Provincial Key Laboratory of Otology, Jinan, P. R. China.) Xianfang Liu老师研究团队在《American Journal of Cancer Research》上发表论文：

“Afatinib down-regulates MCL-1 expression through the PERK-eIF2α-ATF4 axis and leads to apoptosis in head and neck squamous cell carcinoma”

“阿法替尼通过PERK-eIF2α-ATF4轴下调MCL-1表达，导致头颈部鳞状细胞癌细胞凋亡”

Abstract：

Afatinib is the second generation of irreversible inhibitor of EGFR, HER2 and HER4, which has shown encouraging phase II and III clinical outcomes in the treatment of head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanism of afatinib-induced apoptosis in HNSCC is poorly understood. In the present investigation, we discovered that down-regulation of MCL-1, an anti-apoptotic member of BCL-2 family, was responsible for afatinib-triggered apoptosis. And the inactivation of AKT-mTOR signaling caused by afatinib lead to translational inhibition of MCL-1 expression. As a crucial branch of ER stress, PERK-eIF2α-ATF4 axis was also stimulated in HNSCC cells after afatinib incubation. Silencing either eIF2α or ATF4 by siRNA transfection relieved afatinib-caused suppression of AKT-mTOR activity, attenuating MCL-1 down-regulation as well as subsequent apoptosis. Collectively, the results show that afatinib hampers AKT-mTOR activation by stimulating PERK-eIF2α-ATF4 signaling pathway, giving rise to MCL-1 down-regulation mediated apoptosis in HNSCC cells. Therefore, our findings reveal the elaborate molecular network of afatinib-induced apoptosis in HNSCC, which would provide substantial theoretical underpinnings for afatinib clinical application and highlight its promising prospect in HNSCC treatment.

摘要：

Afatinib是第二代不可逆EGFR、HER2和HER4抑制剂，在治疗头颈部鳞状细胞癌(HNSCC)中显示出令人鼓舞的II期和III期临床结果。然而，阿法替尼诱导HNSCC细胞凋亡的分子机制尚不清楚。在本研究中，我们发现BCL-2家族抗凋亡成员MCL-1的下调与阿法替尼引发的细胞凋亡有关。阿法替尼引起的AKT-mTOR信号失活导致MCL-1表达的翻译抑制。作为内质网应激的重要分支，PERK-eIF2α-ATF4轴在阿法替尼培养后也受到刺激。通过siRNA转染沉默eIF2α或ATF4可缓解阿法替尼引起的AKT-mTOR活性抑制，减轻MCL-1下调以及随后的凋亡。综上所述，阿法替尼通过刺激PERK-eIF2α-ATF4信号通路抑制AKT-mTOR的激活，引起MCL-1下调介导的HNSCC细胞凋亡。因此，我们的研究结果揭示了阿法替尼诱导HNSCC细胞凋亡的精细分子网络，为阿法替尼的临床应用提供了坚实的理论基础，并突出了其在HNSCC治疗中的广阔前景。

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