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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...

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Autores principales: Pan, Xiaohui, Li, Run, Guo, Hongjie, Zhang, Wenxin, Xu, Xiaqing, Chen, Xi, Ding, Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
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.
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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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