Xu Yanfeng, Zhao Yinghui, Xu Yanli, Guan Yu, Zhang Xiao, Chen Yan, Wu Qi, Zhu Guoqing, Chen Yuxin, Sun Fenyong, Wang Jiayi, Yu Yongchun
Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, School of Medicine,Shanghai, 200072, China.
Cell Signal. 2017 Jan;29:209-217. doi: 10.1016/j.cellsig.2016.11.001. Epub 2016 Nov 9.
Chemotherapy is critical for the treatment of liver cancer. Despite the pro-apoptotic effects of corosolic acid (CA) have been revealed, the methods to enhance its efficacy are unclear. The aim of this study is to investigate the target that might reduce CA efficacy and figure out the way to conquer it. We found reduction of Yes-associated protein (YAP) might be a critical event that suppresses efficacy of CA. Treatment of CA accelerated degradation of YAP via enhancing its phosphorylation by LATS1. Moreover, we found CA boosts βTrCP-dependent Ubiquitination of YAP. Interestingly, the protein stability of βTrCP per se could be enhanced by CA. Notably, ActionomycinD (AD) strengthened CA-induced apoptosis of liver cancer cells via elevating YAP while down-regulating βTrCP. Importantly, combined treatment of CA and AD had much more obvious influences against transformative phenotypes of liver cancer cells than those under treatment of CA alone. Combined usage of AD successfully reduced IC50 value of CA. In summary, we have first uncovered that suppression of YAP might reduce efficacy of CA to treat liver cancer, combined treatment of AD and CA might solve this problem.
化疗对于肝癌的治疗至关重要。尽管已揭示了熊果酸（CA）的促凋亡作用，但其增效方法尚不清楚。本研究旨在探究可能降低CA疗效的靶点并找出克服该问题的方法。我们发现Yes相关蛋白（YAP）的减少可能是抑制CA疗效的关键事件。CA处理通过增强LATS1对YAP的磷酸化作用加速了YAP的降解。此外，我们发现CA增强了βTrCP依赖的YAP泛素化。有趣的是，CA本身可增强βTrCP的蛋白质稳定性。值得注意的是，放线菌素D（AD）通过上调YAP同时下调βTrCP增强了CA诱导的肝癌细胞凋亡。重要的是，与单独使用CA相比，CA与AD联合治疗对肝癌细胞的转化表型具有更明显的影响。联合使用AD成功降低了CA的半数抑制浓度（IC50）值。总之，我们首次发现抑制YAP可能会降低CA治疗肝癌的疗效，AD与CA联合治疗可能解决这一问题。
