YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63-GPX2 Axis and ROS Accumulation
YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63-GPX2 Axis and ROS Accumulation
复制标题
YAP 通过 DNp63-GPX2 轴失调和 ROS 积累抑制肺鳞状细胞癌进展
DOI：
10.1158/0008-5472.can-17-0449
复制
发表时间：
2017-11-01
期刊：
影响因子：
11.2
通讯作者：
Ji, Hongbin
中科院分区：
文献类型：
--
作者：
Huang, Hsinyi;Zhang, Wenjing;Ji, Hongbin
肺鳞状细胞癌（SCC）约占非小细胞肺癌的30%，通常难以治疗。筛选一个小分子库，我们确定洋地黄毒苷作为一种高效的化合物，在体外和体内抑制人肺SCC的生长。机制研究表明，洋地黄毒苷衰减雅普磷酸化和促进雅普核螯合。雅普激活通过下调抗氧化酶GPX 2以与p63阻断相关的方式导致活性氧（ROS）的过度积累。在患者来源的异种移植物模型中，洋地黄毒苷治疗有效地抑制了肺SCC进展，与雅普表达减少相关。总的来说，我们的研究结果强调了雅普通过下调GPX 2和ROS积累的新的肿瘤抑制功能，具有改善人肺SCC精确医学的潜在意义。(C)2017年AACR。
Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non-small cell lung cancer, is often refractory to therapy. Screening a small-molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor-suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC. (C) 2017 AACR.