Chemical or genetic Pin1 inhibition exerts potent anticancer activity against hepatocellular carcinoma by blocking multiple cancer-driving pathways
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Author
Liao, Xin-Hua
Zhang, Arina Li
Zheng, Min
Li, Mei-Qing
Chen, Champ Peng
Xu, Huijuan
Chu, Qing-Song
Yang, Dayun
Lu, Wenxian
Tsai, Ting-Fen
Liu, Hekun
Zhou, Xiao Zhen
Lu, Kun Ping
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/srep43639Metadata
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Liao, X., A. L. Zhang, M. Zheng, M. Li, C. P. Chen, H. Xu, Q. Chu, et al. 2017. “Chemical or genetic Pin1 inhibition exerts potent anticancer activity against hepatocellular carcinoma by blocking multiple cancer-driving pathways.” Scientific Reports 7 (1): 43639. doi:10.1038/srep43639. http://dx.doi.org/10.1038/srep43639.Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant cancers with high inter- and intra-tumor heterogeneity. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 is prevalently overexpressed in human cancers including ~70% of HCC, and promotes tumorigenesis by activating multiple cancer-driving pathways. However, it was challenging to evaluate the significance of targeting Pin1 in cancer treatment until the recent identification of all-trans retinoic acid (ATRA) as a Pin1 inhibitor. Here we systematically investigate functions of Pin1 and its inhibitor ATRA in the development and treatment of HCC. Pin1 knockdown potently inhibited HCC cell proliferation and tumor growth in mice. ATRA-induced Pin1 degradation inhibited the growth of HCC cells, although at a higher IC50 as compared with breast cancer cells, likely due to more active ATRA metabolism in liver cells. Indeed, inhibition of ATRA metabolism enhanced the sensitivity of HCC cells to ATRA. Moreover, slow-releasing ATRA potently and dose-dependently inhibited HCC growth in mice. Finally, chemical or genetic Pin1 ablation blocked multiple cancer-driving pathways simultaneously in HCC cells. Thus, targeting Pin1 offers a promising therapeutic approach to simultaneously stop multiple cancer-driving pathways in HCC.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337947/pdf/Terms of Use
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