Blocking inhibition to YAP by ActinomycinD enhances anti-tumor efficacy of Corosolic acid in treating liver cancer.
Blocking inhibition to YAP by ActinomycinD enhances anti-tumor efficacy of Corosolic acid in treating liver cancer.
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DOI：
10.1016/j.cellsig.2016.11.001
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发表时间：
2017
影响因子：
4.8
通讯作者：
Yanfeng Xu;Yinghui Zhao;Yanli Xu;Yu Guan;X. Zhang;Yan Chen;Qi Wu;Guoqing Zhu;Yuxin Chen;F. Sun;Jiayi Wang;Yongchun Yu
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文献类型：
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作者：
Yanfeng Xu;Yinghui Zhao;Yanli Xu;Yu Guan;X. Zhang;Yan Chen;Qi Wu;Guoqing Zhu;Yuxin Chen;F. Sun;Jiayi Wang;Yongchun Yu
化疗对肝癌的治疗至关重要。尽管珊瑚醇酸(CA)的促凋亡作用已被揭示，但提高其疗效的方法尚不清楚。本研究的目的是研究可能降低CA疗效的靶点，并找出克服它的方法。我们发现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的磷酸化加速YAP的降解。此外，我们还发现CA促进了依赖βTrCP的YAP泛素化。有趣的是，CA可以提高βTrCP本身的蛋白质稳定性。值得注意的是，放线菌素D(AD)通过上调YAP和下调βTrCP来增强CA诱导的肝癌细胞的凋亡。重要的是，CA和AD联合作用对肝癌细胞转化表型的影响比CA单独作用时明显得多。AD联用成功地降低了CA的IC50值。综上所述，我们首次发现抑制YAP可能会降低CA治疗肝癌的疗效，AD和CA的联合治疗可能会解决这个问题。
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.