State Key Laboratory of Cell Biology, Chinese Academy of Science, Shanghai, China.
CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Science, Shanghai, China.
Cancer Res. 2017 Nov 1;77(21):5769-5781. doi: 10.1158/0008-5472.CAN-17-0449. Epub 2017 Sep 15.
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 and 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. .
肺鳞状细胞癌 (SCC) 约占非小细胞肺癌的 30%，通常对治疗有抗性。在筛选小分子文库时，我们发现洋地黄毒苷是一种高活性化合物，可抑制人肺 SCC 生长。机制研究表明，洋地黄毒苷通过降低抗氧化酶 GPX2 的表达来抑制 YAP 的磷酸化并促进 YAP 的核隔离，从而减少活性氧 (ROS) 的积累。YAP 的激活通过阻断 p63 相关的方式，导致抗氧化酶 GPX2 的表达下调，从而导致 ROS 的过度积累。在患者来源的异种移植模型中，洋地黄毒苷治疗与 YAP 表达降低相关，可有效抑制肺 SCC 的进展。总之，我们的研究结果强调了 YAP 通过下调 GPX2 和 ROS 积累发挥的新型肿瘤抑制功能，这可能对改善人类肺 SCC 的精准医学有意义。
