Small molecule activators of TAK1 promotes its activity-dependent ubiquitination and TRAIL-mediated tumor cell death.
Weimin SunGuowei WuXinyu TianChunting QiJingli LiuYilun TongMengmeng ZhangJiayang GaoZe CaoYuchao ZhangZhijun LiuXiaoxu TianPing WuChao PengJingwen LiLi TanBing ShanJianping LiuYing LiJunying YuanPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
TAK1 is a key modulator of both NF-κB signaling and RIPK1. In TNF signaling pathway, activation of TAK1 directly mediates the phosphorylation of IKK complex and RIPK1. In a search for small molecule activators of RIPK1-mediated necroptosis, we found R406/R788, two small molecule analogs that could promote sustained activation of TAK1. Treatment with R406 sensitized cells to TNF-mediated necroptosis and RIPK1-dependent apoptosis by promoting sustained RIPK1 activation. Using click chemistry and multiple biochemical binding assays, we showed that treatment with R406 promotes the activation of TAK1 by directly binding to TAK1, independent of its original target Syk kinase. Treatment with R406 promoted the ubiquitination of TAK1 and the interaction of activated TAK1 with ubiquitinated RIPK1. Finally, we showed that R406/R788 could promote the cancer-killing activities of TRAIL in vitro and in mouse models. Our studies demonstrate the possibility of developing small molecule TAK1 activators to potentiate the effect of TRAIL as anticancer therapies.
Keyphrases
- small molecule
- signaling pathway
- cell death
- cell cycle arrest
- protein protein
- rheumatoid arthritis
- pi k akt
- oxidative stress
- induced apoptosis
- mouse model
- squamous cell carcinoma
- immune response
- combination therapy
- molecular docking
- lps induced
- young adults
- binding protein
- transcription factor
- papillary thyroid
- smoking cessation