title: Afatinib down-regulates MCL-1 expression through the PERK-eIF2α-ATF4 axis and leads to apoptosis in head and neck squamous cell carcinoma.
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.
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, P. R. China; Shandong Provincial Key Laboratory of OtologyJinan, P. R. China.
authors.forename: Xianfang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University Jinan, P. R. China.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University Jinan, P. R. China.
authors.forename: Jidong
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, P. R. China; Shandong Provincial Key Laboratory of OtologyJinan, P. R. China.
authors.forename: Xiuxiu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University Jinan, P. R. China.
authors.forename: Juke
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University Jinan, P. R. China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University Jinan, P. R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Sa
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University Jinan, P. R. China.
authors.forename: Peihang
authors.initials: P
authors.lastname: Jing
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, P. R. China; Shandong Provincial Key Laboratory of OtologyJinan, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
keywords: ATF4; Afatinib; MCL-1; PERK; apoptosis; eIF2α