Doxycycline directly targets PAR1 to suppress tumor progression
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Weilong Zhong1,*, Shuang Chen2,*, Qiang Zhang1,*, Ting Xiao1,*, Yuan Qin1, Ju Gu1, Bo Sun2, Yanrong Liu2, Xiangyan Jing1, Xuejiao Hu1, Peng Zhang1, Honggang Zhou1,2, Tao Sun1,2, Cheng Yang1,2
1State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300000, China
2Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, 300000, China
*These authors contributed equally to this work
Tao Sun, email: firstname.lastname@example.org
Cheng Yang, email: email@example.com
Keywords: tumor, molecular target, GPCR, tumor progression, antibotics
Received: November 23, 2016 Accepted: January 24, 2017 Published: February 07, 2017
Doxycycline have been reported to exert anti-cancer activity and have been assessed as anti-cancer agents in clinical trials. However, the direct targets of doxycycline in cancer cells remain unclear. In this study, we used a chemical proteomics approach to identify the Protease-activated receptor 1 (PAR1) as a specific target of inhibition of doxycycline. Binding assays and single-molecule imaging assays were performed to confirm the inhibition of doxycycline to PAR1. The effect of doxycycline on multi-omics and cell functions were assessed based on a PAR1/thrombin model. Molecular docking and molecular dynamic simulations revealed that doxycycline interacts with key amino acids in PAR1. Mutation of PAR1 further confirmed the computation-based results. Moreover, doxycycline provides highly selective inhibition of PAR1 signaling in tumors in vitro and in vivo. Using pathological clinical samples co-stained for doxycycline and PAR1, it was found that doxycycline fluorescence intensity and PAR1 expression shown a clear positive correlation. Thus, doxycycline may be a useful targeted anti-cancer drug that should be further investigated in clinical trials.
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