Lin Yu-Chin, Wu Meng-Hsuan, Wei Tzu-Tang, Lin Yun-Chieh, Huang Wen-Chih, Huang Liang-Yu, Lin Yi-Ting, Chen Ching-Chow
Oncotarget. 2014 Jan 15;5(1):298-308. doi: 10.18632/oncotarget.1628.
Head and neck squamous cell carcinoma (HNSCC) is an important endemic disease in Taiwan with aggressive course and dismal outcome. Dasatinib is a Bcr-bl and Src kinase inhibitor that has potential against HNSCC. We recently disclosed that EGFR degradation is critical for dasatinib-induced apoptosis. Here, we further demonstrate that AMPK-dependent ER stress is responsible for this event. Dasatinib induced ER stress which mediated EGFR degradation in a c-cbl-dependent manner. AMPK activation induced by dasatinib might be due to ATP decrease through the up-regulation of pyruvate dehydrogenase kinase 4 (PDK4). Furthermore, activation of AMPK by metformin sensitized dasatinib-induced in vitro and in vivo anti-cancer effect. The correlation of AMPK activation and EGFR expression was seen in HNSCC cells and human tumor specimens. Our results disclose that AMPK-dependent ER stress plays a crucial role in the anti-cancer effect of dasatinib in HNSCC and further activation of AMPK by metformin might enhance dasatinib efficacy.
头颈鳞状细胞癌（HNSCC）是台湾地区一种重要的地方病，病程进展迅速，预后不佳。达沙替尼是一种Bcr-bl和Src激酶抑制剂，对HNSCC具有潜在疗效。我们最近发现，表皮生长因子受体（EGFR）降解对于达沙替尼诱导的细胞凋亡至关重要。在此，我们进一步证明，AMP激活蛋白激酶（AMPK）依赖性内质网应激对此事件负责。达沙替尼诱导内质网应激，以内皮细胞蛋白酪氨酸磷酸酶（c-cbl）依赖性方式介导EGFR降解。达沙替尼诱导的AMPK激活可能是由于丙酮酸脱氢酶激酶4（PDK4）上调导致三磷酸腺苷（ATP）减少。此外，二甲双胍激活AMPK可增强达沙替尼在体外和体内的抗癌作用。在HNSCC细胞和人类肿瘤标本中观察到AMPK激活与EGFR表达之间的相关性。我们的结果表明，AMPK依赖性内质网应激在达沙替尼对HNSCC的抗癌作用中起关键作用，二甲双胍进一步激活AMPK可能增强达沙替尼的疗效。
