Original articles
Yang Liu, Xiaojia Liu, Na Zhang, Mingxiao Yin, Jingwen Dong, Qingxuan Zeng, Genxiang Mao, Danqing Song, Lu Liu, Hongbin Deng. Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5[J]. Acta Pharmaceutica Sinica B, 2020, 10(12): 2299-2312

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5
Yang Liua, Xiaojia Liua, Na Zhanga, Mingxiao Yina, Jingwen Donga, Qingxuan Zenga, Genxiang Maoc, Danqing Songa, Lu Liud, Hongbin Denga,b
a Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100050, China;
b State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
c Zhejiang Provincial Key Lab of Geriatrics, Department of Geriatrics, Zhejiang Hospital, Hangzhou 310013, China;
d Qingdao Women and Children's Hospital, Qingdao University, Qingdao 266034, China
Abstract:
Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PDL1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.
Key words:    PD-L1    Immune checkpoint blockade    COP9 signalosome 5    Berberine;PD-1/PD-L1 axis    T-cell immunity   
Received: 2020-03-26     Revised: 2020-06-11
DOI: 10.1016/j.apsb.2020.06.014
Funds: This study was supported by grants from National Natural Science Foundation of China (81973366, 81773782 and 81903695), CAMS Innovation Fund for Medical Sciences (2016-12M-1-011, China), Open Project of State Key Laboratory of Bioactive Substance and Function of Natural Medicines (GTZK201908, China), National Mega-project for Innovative Drugs (2019ZX09721-001, China) and Chinese Pharmaceutical Association-Yiling Pharmaceutical Innovation Fund for Biomedicine (GL-1-B04-20180366, China).
Corresponding author: Lu Liu, liulu208@163.com;Hongbin Deng, hdeng@imb.pumc.edu.cn     Email:liulu208@163.com;hdeng@imb.pumc.edu.cn
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Yang Liu
Xiaojia Liu
Na Zhang
Mingxiao Yin
Jingwen Dong
Qingxuan Zeng
Genxiang Mao
Danqing Song
Lu Liu
Hongbin Deng

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