Cargando…

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5

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 (...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Yang, Liu, Xiaojia, Zhang, Na, Yin, Mingxiao, Dong, Jingwen, Zeng, Qingxuan, Mao, Genxiang, Song, Danqing, Liu, Lu, Deng, Hongbin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745128/
https://www.ncbi.nlm.nih.gov/pubmed/33354502
http://dx.doi.org/10.1016/j.apsb.2020.06.014
_version_ 1783624553279258624
author Liu, Yang
Liu, Xiaojia
Zhang, Na
Yin, Mingxiao
Dong, Jingwen
Zeng, Qingxuan
Mao, Genxiang
Song, Danqing
Liu, Lu
Deng, Hongbin
author_facet Liu, Yang
Liu, Xiaojia
Zhang, Na
Yin, Mingxiao
Dong, Jingwen
Zeng, Qingxuan
Mao, Genxiang
Song, Danqing
Liu, Lu
Deng, Hongbin
author_sort Liu, Yang
collection PubMed
description 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 PD-L1 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.
format Online
Article
Text
id pubmed-7745128
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-77451282020-12-21 Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5 Liu, Yang Liu, Xiaojia Zhang, Na Yin, Mingxiao Dong, Jingwen Zeng, Qingxuan Mao, Genxiang Song, Danqing Liu, Lu Deng, Hongbin Acta Pharm Sin B Original Article 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 PD-L1 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. Elsevier 2020-12 2020-06-30 /pmc/articles/PMC7745128/ /pubmed/33354502 http://dx.doi.org/10.1016/j.apsb.2020.06.014 Text en © 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Liu, Yang
Liu, Xiaojia
Zhang, Na
Yin, Mingxiao
Dong, Jingwen
Zeng, Qingxuan
Mao, Genxiang
Song, Danqing
Liu, Lu
Deng, Hongbin
Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5
title Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5
title_full Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5
title_fullStr Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5
title_full_unstemmed Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5
title_short Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5
title_sort berberine diminishes cancer cell pd-l1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of csn5
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745128/
https://www.ncbi.nlm.nih.gov/pubmed/33354502
http://dx.doi.org/10.1016/j.apsb.2020.06.014
work_keys_str_mv AT liuyang berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5
AT liuxiaojia berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5
AT zhangna berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5
AT yinmingxiao berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5
AT dongjingwen berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5
AT zengqingxuan berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5
AT maogenxiang berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5
AT songdanqing berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5
AT liulu berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5
AT denghongbin berberinediminishescancercellpdl1expressionandfacilitatesantitumorimmunityviainhibitingthedeubiquitinationactivityofcsn5