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SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1
BACKGROUND: Programmed death-ligand 1 (PD-L1) is a T-cell inhibitory checkpoint molecule that suppresses antitumor immunity. Anti-PD-L1 antibodies have shown remarkable promise in treating tumors, but the patient response rate is low. Therefore, small-molecule checkpoint inhibitors blocking PD-L1 fu...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414307/ https://www.ncbi.nlm.nih.gov/pubmed/30711516 http://dx.doi.org/10.1016/j.ebiom.2019.01.054 |
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author | Zhang, Na Dou, Yueying Liu, Lu Zhang, Xin Liu, Xiaojia Zeng, Qingxuan Liu, Yang Yin, Mingxiao Liu, Xiujun Deng, Hongbin Song, Danqing |
author_facet | Zhang, Na Dou, Yueying Liu, Lu Zhang, Xin Liu, Xiaojia Zeng, Qingxuan Liu, Yang Yin, Mingxiao Liu, Xiujun Deng, Hongbin Song, Danqing |
author_sort | Zhang, Na |
collection | PubMed |
description | BACKGROUND: Programmed death-ligand 1 (PD-L1) is a T-cell inhibitory checkpoint molecule that suppresses antitumor immunity. Anti-PD-L1 antibodies have shown remarkable promise in treating tumors, but the patient response rate is low. Therefore, small-molecule checkpoint inhibitors blocking PD-L1 function are urgently needed. METHODS: Changes of protein expression and phosphorylation levels were determined by immunoblotting. The level of Membrane PD-L1 was examined by flow cytometer. Cytotoxicity of T cells and NK cells toward tumor cells were detected using LDH and cell index assays. Lysosome function was investigated by NAG assay. Changes in lysosomal-related genes were measured by RT-PCR. In vivo anti-NSCLC cancer effects were assessed using C57BL/6 mice bearing Lewis tumor xenografts. FINDINGS: We identified SA-49 as a new regulator of PD-L1 expression from a series of novel aloperine derivatives. SA-49 decreased the expression of PD-L1 in NSCLC cells and enhanced the cytotoxicity of co-cultured T and NK cells toward tumor cells. Importantly, lysosomal pathway contributed to SA-49-mediated down-regulation of PD-L1. SA-49 increased the biogenesis of lysosome and promoted translocation of PD-L1 to lysosome for proteolysis, which was associated with nuclear translocation of MITF. SA-49-induced MITF translocation acted through activation of PKCα and subsequently suppression of GSK3β activity. Furthermore, SA-49 suppressed Lewis tumor xenograft growth by activating immune microenvironment in C57BL/6 mice. INTERPRETATION: Our data demonstrate that SA-49 can be used to regulate PD-L1 in cancer cells and trigger its degradation by activating lysosome function. |
format | Online Article Text |
id | pubmed-6414307 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-64143072019-03-22 SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1 Zhang, Na Dou, Yueying Liu, Lu Zhang, Xin Liu, Xiaojia Zeng, Qingxuan Liu, Yang Yin, Mingxiao Liu, Xiujun Deng, Hongbin Song, Danqing EBioMedicine Research paper BACKGROUND: Programmed death-ligand 1 (PD-L1) is a T-cell inhibitory checkpoint molecule that suppresses antitumor immunity. Anti-PD-L1 antibodies have shown remarkable promise in treating tumors, but the patient response rate is low. Therefore, small-molecule checkpoint inhibitors blocking PD-L1 function are urgently needed. METHODS: Changes of protein expression and phosphorylation levels were determined by immunoblotting. The level of Membrane PD-L1 was examined by flow cytometer. Cytotoxicity of T cells and NK cells toward tumor cells were detected using LDH and cell index assays. Lysosome function was investigated by NAG assay. Changes in lysosomal-related genes were measured by RT-PCR. In vivo anti-NSCLC cancer effects were assessed using C57BL/6 mice bearing Lewis tumor xenografts. FINDINGS: We identified SA-49 as a new regulator of PD-L1 expression from a series of novel aloperine derivatives. SA-49 decreased the expression of PD-L1 in NSCLC cells and enhanced the cytotoxicity of co-cultured T and NK cells toward tumor cells. Importantly, lysosomal pathway contributed to SA-49-mediated down-regulation of PD-L1. SA-49 increased the biogenesis of lysosome and promoted translocation of PD-L1 to lysosome for proteolysis, which was associated with nuclear translocation of MITF. SA-49-induced MITF translocation acted through activation of PKCα and subsequently suppression of GSK3β activity. Furthermore, SA-49 suppressed Lewis tumor xenograft growth by activating immune microenvironment in C57BL/6 mice. INTERPRETATION: Our data demonstrate that SA-49 can be used to regulate PD-L1 in cancer cells and trigger its degradation by activating lysosome function. Elsevier 2019-01-31 /pmc/articles/PMC6414307/ /pubmed/30711516 http://dx.doi.org/10.1016/j.ebiom.2019.01.054 Text en © 2019 The Authors. Published 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 | Research paper Zhang, Na Dou, Yueying Liu, Lu Zhang, Xin Liu, Xiaojia Zeng, Qingxuan Liu, Yang Yin, Mingxiao Liu, Xiujun Deng, Hongbin Song, Danqing SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1 |
title | SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1 |
title_full | SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1 |
title_fullStr | SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1 |
title_full_unstemmed | SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1 |
title_short | SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1 |
title_sort | sa-49, a novel aloperine derivative, induces mitf-dependent lysosomal degradation of pd-l1 |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414307/ https://www.ncbi.nlm.nih.gov/pubmed/30711516 http://dx.doi.org/10.1016/j.ebiom.2019.01.054 |
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