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Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1
Programmed death ligand 1 (PD-L1) which is upregulated in various epithelial tumors, plays a central role in the evasion of the immune system. In addition to monoclonal antibodies that blocking PD1/PD-L1 axis, finding small molecule compounds that can suppress PD-L1 expression might be another subst...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838064/ https://www.ncbi.nlm.nih.gov/pubmed/33519429 http://dx.doi.org/10.3389/fphar.2020.539261 |
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author | Pan, Xiaohui Li, Run Guo, Hongjie Zhang, Wenxin Xu, Xiaqing Chen, Xi Ding, Ling |
author_facet | Pan, Xiaohui Li, Run Guo, Hongjie Zhang, Wenxin Xu, Xiaqing Chen, Xi Ding, Ling |
author_sort | Pan, Xiaohui |
collection | PubMed |
description | Programmed death ligand 1 (PD-L1) which is upregulated in various epithelial tumors, plays a central role in the evasion of the immune system. In addition to monoclonal antibodies that blocking PD1/PD-L1 axis, finding small molecule compounds that can suppress PD-L1 expression might be another substitutable strategy for PD1/PD-L1 based therapy. Here, we found that dihydropyridine calcium channel blockers dose-dependently reduced the expression of PD-L1, both in the cytoplasm and cell surface. IFNγ induced PD-L1 transcription was consistently suppressed by Lercanidipine in 24 h, whereas, the half-life of PD-L1 protein was not significantly affected. IFNγ trigged significant STAT1 phosphorylation, which was eliminated by Lercanidipine. Similarly, STAT1 phosphorylation could also be abolished by extracellular calcium chelating agent EGTA and intracellular calcium chelator BAPTA-AM. Furthermore, Lercanidipine enhanced killing ability of T cells by down-regulating PD-L1. Taken together, our studies suggest that calcium signal is a crucial factor that mediates the transcription of PD-L1 and regulation of calcium can be used as a potential strategy for PD-L1 inhibition. |
format | Online Article Text |
id | pubmed-7838064 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78380642021-01-28 Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1 Pan, Xiaohui Li, Run Guo, Hongjie Zhang, Wenxin Xu, Xiaqing Chen, Xi Ding, Ling Front Pharmacol Pharmacology Programmed death ligand 1 (PD-L1) which is upregulated in various epithelial tumors, plays a central role in the evasion of the immune system. In addition to monoclonal antibodies that blocking PD1/PD-L1 axis, finding small molecule compounds that can suppress PD-L1 expression might be another substitutable strategy for PD1/PD-L1 based therapy. Here, we found that dihydropyridine calcium channel blockers dose-dependently reduced the expression of PD-L1, both in the cytoplasm and cell surface. IFNγ induced PD-L1 transcription was consistently suppressed by Lercanidipine in 24 h, whereas, the half-life of PD-L1 protein was not significantly affected. IFNγ trigged significant STAT1 phosphorylation, which was eliminated by Lercanidipine. Similarly, STAT1 phosphorylation could also be abolished by extracellular calcium chelating agent EGTA and intracellular calcium chelator BAPTA-AM. Furthermore, Lercanidipine enhanced killing ability of T cells by down-regulating PD-L1. Taken together, our studies suggest that calcium signal is a crucial factor that mediates the transcription of PD-L1 and regulation of calcium can be used as a potential strategy for PD-L1 inhibition. Frontiers Media S.A. 2021-01-13 /pmc/articles/PMC7838064/ /pubmed/33519429 http://dx.doi.org/10.3389/fphar.2020.539261 Text en Copyright © 2021 Pan, Li, Guo, Zhang, Xu, Chen and Ding. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Pan, Xiaohui Li, Run Guo, Hongjie Zhang, Wenxin Xu, Xiaqing Chen, Xi Ding, Ling Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1 |
title | Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1 |
title_full | Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1 |
title_fullStr | Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1 |
title_full_unstemmed | Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1 |
title_short | Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1 |
title_sort | dihydropyridine calcium channel blockers suppress the transcription of pd-l1 by inhibiting the activation of stat1 |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838064/ https://www.ncbi.nlm.nih.gov/pubmed/33519429 http://dx.doi.org/10.3389/fphar.2020.539261 |
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