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MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells
Natural killer (NK) cells recognize stress-activated NK group 2, member D (NKG2D) ligands in tumors. In the present study, the expression levels of NKG2D ligands were examined in four lung cancer cell lines (A549, PLA801D, NCI-H157 and NCI-H520). In the A549 cells, the expression of MHC class I poly...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297755/ https://www.ncbi.nlm.nih.gov/pubmed/30483783 http://dx.doi.org/10.3892/mmr.2018.9676 |
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author | Luo, Dan Dong, Xi-Wen Yan, Bing Liu, Mei Xue, Tian-Hui Liu, Hui You, Jun-Hao Li, Fang Wang, Zi-Ling Chen, Zhi-Nan |
author_facet | Luo, Dan Dong, Xi-Wen Yan, Bing Liu, Mei Xue, Tian-Hui Liu, Hui You, Jun-Hao Li, Fang Wang, Zi-Ling Chen, Zhi-Nan |
author_sort | Luo, Dan |
collection | PubMed |
description | Natural killer (NK) cells recognize stress-activated NK group 2, member D (NKG2D) ligands in tumors. In the present study, the expression levels of NKG2D ligands were examined in four lung cancer cell lines (A549, PLA801D, NCI-H157 and NCI-H520). In the A549 cells, the expression of MHC class I polypeptiderelated sequence (MIC)A/B and UL16 binding protein (ULBP)1 was weak, the expression of ULBP2 was typical, and neither ULBP3 nor ULBP4 were expressed. The mechanism underlying the regulatory effect of a cancer treatment agent on the expression of NKG2D ligands was investigated using the proteasome inhibitor MG132. Following treatment for 8 h with MG132, the transcription levels of MICB and ULBP1 were upregulated 10.62- and 11.09-fold, respectively, and the expression levels of MICB and ULBP1 were increased by 68.18 and 23.65%, respectively. Notably, MICB exhibited significant time-dependent change. MG132 increased the transcription of MICB by acting at a site in the 480-bp MICB upstream promoter. The activity of the MICB promoter was upregulated 1.77-fold following treatment with MG132. MG132 treatment improved the cytotoxicity of NK cells, which was partially blocked by an antibody targeting NKG2D, and more specifically the MICB molecule. The expression of MICB induced by MG132 was inhibited by KU-55933 [ataxia telangiectasia mutated (ATM) kinase inhibitor], wortmannin (phosphoinositide 3 kinase inhibitor) and caffeine (ATM/ATM-Rad3-related inhibitor). The phosphorylation of checkpoint kinase 2 (Chk2), an event associated with DNA damage, was observed following treatment with MG132. These results indicated that MG132 selectively upregulates the expression of MICB in A549 cells, and increases the NKG2D-mediated cytotoxicity of NK cells. The regulatory effect of MG132 may be associated with the activation of Chk2, an event associated with DNA damage. The combination of MG132 with NK cell immunotherapy may have a synergistic effect that improves the therapeutic effect of lung cancer treatment. |
format | Online Article Text |
id | pubmed-6297755 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-62977552018-12-26 MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells Luo, Dan Dong, Xi-Wen Yan, Bing Liu, Mei Xue, Tian-Hui Liu, Hui You, Jun-Hao Li, Fang Wang, Zi-Ling Chen, Zhi-Nan Mol Med Rep Articles Natural killer (NK) cells recognize stress-activated NK group 2, member D (NKG2D) ligands in tumors. In the present study, the expression levels of NKG2D ligands were examined in four lung cancer cell lines (A549, PLA801D, NCI-H157 and NCI-H520). In the A549 cells, the expression of MHC class I polypeptiderelated sequence (MIC)A/B and UL16 binding protein (ULBP)1 was weak, the expression of ULBP2 was typical, and neither ULBP3 nor ULBP4 were expressed. The mechanism underlying the regulatory effect of a cancer treatment agent on the expression of NKG2D ligands was investigated using the proteasome inhibitor MG132. Following treatment for 8 h with MG132, the transcription levels of MICB and ULBP1 were upregulated 10.62- and 11.09-fold, respectively, and the expression levels of MICB and ULBP1 were increased by 68.18 and 23.65%, respectively. Notably, MICB exhibited significant time-dependent change. MG132 increased the transcription of MICB by acting at a site in the 480-bp MICB upstream promoter. The activity of the MICB promoter was upregulated 1.77-fold following treatment with MG132. MG132 treatment improved the cytotoxicity of NK cells, which was partially blocked by an antibody targeting NKG2D, and more specifically the MICB molecule. The expression of MICB induced by MG132 was inhibited by KU-55933 [ataxia telangiectasia mutated (ATM) kinase inhibitor], wortmannin (phosphoinositide 3 kinase inhibitor) and caffeine (ATM/ATM-Rad3-related inhibitor). The phosphorylation of checkpoint kinase 2 (Chk2), an event associated with DNA damage, was observed following treatment with MG132. These results indicated that MG132 selectively upregulates the expression of MICB in A549 cells, and increases the NKG2D-mediated cytotoxicity of NK cells. The regulatory effect of MG132 may be associated with the activation of Chk2, an event associated with DNA damage. The combination of MG132 with NK cell immunotherapy may have a synergistic effect that improves the therapeutic effect of lung cancer treatment. D.A. Spandidos 2019-01 2018-11-20 /pmc/articles/PMC6297755/ /pubmed/30483783 http://dx.doi.org/10.3892/mmr.2018.9676 Text en Copyright: © Luo et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Luo, Dan Dong, Xi-Wen Yan, Bing Liu, Mei Xue, Tian-Hui Liu, Hui You, Jun-Hao Li, Fang Wang, Zi-Ling Chen, Zhi-Nan MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells |
title | MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells |
title_full | MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells |
title_fullStr | MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells |
title_full_unstemmed | MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells |
title_short | MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells |
title_sort | mg132 selectively upregulates micb through the dna damage response pathway in a549 cells |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297755/ https://www.ncbi.nlm.nih.gov/pubmed/30483783 http://dx.doi.org/10.3892/mmr.2018.9676 |
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