College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea.
Department of Otolaryngology-Head and Neck Surgery, Center for Thyroid Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
Biochim Biophys Acta Mol Cell Res. 2023 Dec;1870(8):119556. doi: 10.1016/j.bbamcr.2023.119556. Epub 2023 Aug 5.
Several diseases are associated with improper regulation of the Hippo pathway, which plays an important role in cell proliferation and cancer metastasis. Overactivation of the YAP and TAZ proteins accelerates cell proliferation, invasion, and migration during tumorigenesis. Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits activity against various types of cancer. In this study, we observed that TA decreased YAP and TAZ protein levels in cancer cells. TA increased the phosphorylation of YAP and TAZ, leading to the degradation of YAP and TAZ in the cytoplasm and nucleus. TA predominantly affected multiple phosphodegron sites in the YAP and TAZ and lowered 14-3-3β protein expression, causing YAP and TAZ to enter the ubiquitination pathway. Proteins that affect YAP and TAZ regulation, such as NAG-1 and several YAP/TAZ E3 ligases, were not involved in TA-mediated YAP/TAZ degradation. In summary, our results indicate that TA affects phosphodegron sites on YAP/TAZ, demonstrating a novel effect of TA in tumorigenesis.
几种疾病与 Hippo 通路的异常调节有关，该通路在细胞增殖和癌症转移中发挥着重要作用。YAP 和 TAZ 蛋白的过度激活会加速肿瘤发生过程中的细胞增殖、侵袭和迁移。托芬那酸（TA）是一种非甾体抗炎药（NSAID），对多种类型的癌症具有活性。在本研究中，我们观察到 TA 降低了癌细胞中 YAP 和 TAZ 蛋白水平。TA 增加了 YAP 和 TAZ 的磷酸化，导致 YAP 和 TAZ 在细胞质和核内降解。TA 主要影响 YAP 和 TAZ 的多个磷酸化降解位点，并降低 14-3-3β 蛋白表达，使 YAP 和 TAZ 进入泛素化途径。影响 YAP 和 TAZ 调节的蛋白质，如 NAG-1 和几种 YAP/TAZ E3 连接酶，不参与 TA 介导的 YAP/TAZ 降解。总之，我们的结果表明 TA 影响 YAP/TAZ 的磷酸化降解位点，显示了 TA 在肿瘤发生中的新作用。
