Blocking inhibition to YAP by ActinomycinD enhances anti-tumor efficacy of Corosolic acid in treating liver cancer.
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.
Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
Yanfeng
Y
Xu
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, School of Medicine,Shanghai, 200072, China.
Yinghui
Y
Zhao
Department of Pharmacy, Dongjing Town Community Health Service Center of Songjiang District, Shanghai, 201619, China.
Yanli
Y
Xu
Department of Experiment Centre, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
Yu
Y
Guan
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, School of Medicine,Shanghai, 200072, China.
Xiao
X
Zhang
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, School of Medicine,Shanghai, 200072, China.
Yan
Y
Chen
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, School of Medicine,Shanghai, 200072, China.
Qi
Q
Wu
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, School of Medicine,Shanghai, 200072, China.
Guoqing
G
Zhu
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, School of Medicine,Shanghai, 200072, China.
Yuxin
Y
Chen
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, School of Medicine,Shanghai, 200072, China.
Fenyong
F
Sun
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, School of Medicine,Shanghai, 200072, China; Tongji University Advanced Institute of Translational Medicine, Shanghai, 200092, China. Electronic address: karajan2@163.com.
Jiayi
J
Wang
Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China. Electronic address: yueyongchun88@163.com.
Yongchun
Y
Yu
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D003609:Dactinomycin / Q000494:pharmacology / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008819:Mice, Nude; D008954:Models, Biological; D010641:Phenotype; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D014157:Transcription Factors; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D054875:Ubiquitination / Q000187:drug effects; D000091102:YAP-Signaling Proteins; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D010750:Phosphoproteins; D014157:Transcription Factors; D014315:Triterpenes; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D044844:beta-Transducin Repeat-Containing Proteins; D003609:Dactinomycin; C113861:corosolic acid; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases
Chemotherapy; Protein stability; Transformative phenotypes; YAP; βTrCP