Afatinib induces pro-survival autophagy and increases sensitivity to apoptosis in stem-like HNSCC cells.
Afatinib induces pro-survival autophagy and increases sensitivity to apoptosis in stem-like HNSCC cells.
复制标题
阿法替尼诱导促存活自噬并增加干细胞样 HNSCC 细胞对细胞凋亡的敏感性
DOI：
10.1038/s41419-021-04011-0
复制
发表时间：
2021-07-22
影响因子：
9
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
Liu X;Suo H;Zhou S;Hou Z;Bu M;Liu X;Xu W
阿法替尼是第二代酪氨酸激酶抑制剂（TKI），通过抑制mTORC 1诱导内源性细胞凋亡，在头颈部鳞状细胞癌（HNSCC）中发挥抗肿瘤作用。然而，阿法替尼诱导HNSCC自噬的详细机制和生物学意义仍不清楚。在本研究中，我们证明了阿法替尼在HNSCC细胞中诱导mTORC 1抑制介导的自噬。进一步的机制研究显示，阿法替尼刺激REDD 1-TSC 1信号传导，导致mTORC 1失活和随后的自噬。此外，阿法替尼引起的ROS生成是REDD 1-TSC 1-mTORC 1轴诱导的原因。此外，自噬的药理学或遗传抑制使HNSCC细胞对阿法替尼诱导的细胞凋亡敏感，表明阿法替尼激活了HNSCC细胞中的促生存自噬。重要的是，体外和体内试验表明，阿法替尼在通过CDH 1敲低构建的干细胞样HNSCC细胞中引起细胞凋亡增强，但自噬减弱。这表明阻断自噬有可能成为靶向HNSCC干细胞的有希望的策略。总之，我们的研究结果表明，阿法替尼和自噬抑制剂联合治疗有可能根除HNSCC细胞，特别是临床治疗中的癌症干细胞。
Afatinib, a second-generation tyrosine kinase inhibitor (TKI), exerts its antitumor effects in head and neck squamous cell carcinoma (HNSCC) by inducing intrinsic apoptosis through suppression of mTORC1. However, the detailed mechanism and biological significance of afatinib-induced autophagy in HNSCC remains unclear. In the present study, we demonstrated that afatinib induced mTORC1 suppression-mediated autophagy in HNSCC cells. Further mechanistic investigation revealed that afatinib stimulated REDD1-TSC1 signaling, giving rise to mTORC1 inactivation and subsequent autophagy. Moreover, ROS generation elicited by afatinib was responsible for the induction of the REDD1-TSC1-mTORC1 axis. In addition, pharmacological or genetic inhibition of autophagy sensitized HNSCC cells to afatinib-induced apoptosis, demonstrating that afatinib activated pro-survival autophagy in HNSCC cells. Importantly, in vitro and in vivo assays showed that afatinib caused enhanced apoptosis but weaker autophagy in stem-like HNSCC cells constructed by CDH1 knockdown. This suggested that blocking autophagy has the potential to serve as a promising strategy to target HNSCC stem cells. In conclusion, our findings suggested that the combination treatment with afatinib and autophagy inhibitors has the potential to eradicate HNSCC cells, especially cancer stem cells in clinical therapy.
登录
查看更多内容
影响因子：
78.5
作者：
Mathew, Robin;Karantza-Wadsworth, Vassiliki;White, Eileen
通讯作者：
White, Eileen
影响因子：
51.1
作者：
Machiels, Jean-Pascal H.;Haddad, Robert I.;Cohen, Ezra E. W.
通讯作者：
Cohen, Ezra E. W.
影响因子：
--
作者：
Chao TT;Wang CY;Chen YL;Lai CC;Chang FY;Tsai YT;Chao CH;Shiau CW;Huang YC;Yu CJ;Chen KF
通讯作者：
Chen KF
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Ward, Elizabeth
通讯作者：
Ward, Elizabeth