ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 Inversely Regulates Programmed Death-Ligand 1 Through Negative Feedback of Phosphorylated Epithelial Growth Factor Receptor and Activation of Nuclear Factor-Kappa B in Non-Small Cell Lung Cancer
Naohisa Chiba,1 Toshi Menju,1 Yumeta Shimazu,1 Toshiya Toyazaki,1 Ryota Sumitomo,1 Hideaki Miyamoto,1 Shigeyuki Tamari,1,2 Shigeto Nishikawa,1 Hiroshi Date1 1Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Thoracic Surgery, Shizuoka City Sh...
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Dove Medical Press
2025-01-01
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| author | Chiba N Menju T Shimazu Y Toyazaki T Sumitomo R Miyamoto H Tamari S Nishikawa S Date H |
| author_facet | Chiba N Menju T Shimazu Y Toyazaki T Sumitomo R Miyamoto H Tamari S Nishikawa S Date H |
| author_sort | Chiba N |
| collection | DOAJ |
| description | Naohisa Chiba,1 Toshi Menju,1 Yumeta Shimazu,1 Toshiya Toyazaki,1 Ryota Sumitomo,1 Hideaki Miyamoto,1 Shigeyuki Tamari,1,2 Shigeto Nishikawa,1 Hiroshi Date1 1Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Thoracic Surgery, Shizuoka City Shizuoka Hospital, Shizuoka, JapanCorrespondence: Toshi Menju, Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Shigoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan, Tel +81-757514975, Email toshimnj@kuhp.kyoto-u.ac.jpBackground: Signaling pathways centered on the G-protein ADP-ribosylation factor 6 (Arf6) and its downstream effector ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 (AMAP1) drive cancer invasion, metastasis, and therapy resistance. The Arf6-AMAP1 pathway has been reported to promote receptor recycling leading to programmed cell death-ligand 1 (PD-L1) overexpression in pancreatic ductal carcinoma. Moreover, AMAP1 regulates of nuclear factor-kappa B (NF-κB), which is an important molecule in inflammation and immune activation, including tumor immune interaction through PD-L1 regulation. In this study, we investigated the function of AMAP1 on PD-L1 expression using lung cancer cells.Methods: We used two non-small cell lung cancer cell lines. Protein expression was evaluated by Western blotting. AMAP1 and NF-kB expression were reduced by conventional siRNA methods, and osimertinib was used as an epithelial growth factor receptor (EGFR) inhibitor. Multiple analysis of receptor tyrosine kinases (RTKs) was conducted using a semi-comprehensive RTKs assay.Results: We found that AMAP1 inversely regulated PD-L1 expression. Based on these results, we examined the activation levels of RTKs associated with both AMAP1 and PD-L1. Following a semi-comprehensive phosphorylated RTK assay, we observed the upregulation of phosphorylated EGFR (pEGFR) led by the downregulation of AMAP1. The inhibition of pEGFR by osimertinib downregulates PD-L1 expression. We investigated the relationships between AMAP1, NF-κB, and PD-L1 expression. AMAP1 knockdown upregulated the expression of both NF-κB and PD-L1. Subsequently, NF-κB knockdown downregulated PD-L1 levels, while double knockdown of AMAP1 and NF-κB, restored PD-L1 expression.Conclusion: AMAP1 may inversely regulate PD-L1 through negative feedback of pEGFR and activation of NF-κB in NSCLC cell lines.Keywords: AMAP1, PD-L1, NF-κB, pEGFR |
| format | Article |
| id | doaj-art-88471a6391e8444b99e7dbd2efc8ad5a |
| institution | Kabale University |
| issn | 1179-1322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Dove Medical Press |
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| series | Cancer Management and Research |
| spelling | doaj-art-88471a6391e8444b99e7dbd2efc8ad5a2025-01-21T16:58:06ZengDove Medical PressCancer Management and Research1179-13222025-01-01Volume 179110299379ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 Inversely Regulates Programmed Death-Ligand 1 Through Negative Feedback of Phosphorylated Epithelial Growth Factor Receptor and Activation of Nuclear Factor-Kappa B in Non-Small Cell Lung CancerChiba NMenju TShimazu YToyazaki TSumitomo RMiyamoto HTamari SNishikawa SDate HNaohisa Chiba,1 Toshi Menju,1 Yumeta Shimazu,1 Toshiya Toyazaki,1 Ryota Sumitomo,1 Hideaki Miyamoto,1 Shigeyuki Tamari,1,2 Shigeto Nishikawa,1 Hiroshi Date1 1Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Thoracic Surgery, Shizuoka City Shizuoka Hospital, Shizuoka, JapanCorrespondence: Toshi Menju, Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Shigoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan, Tel +81-757514975, Email toshimnj@kuhp.kyoto-u.ac.jpBackground: Signaling pathways centered on the G-protein ADP-ribosylation factor 6 (Arf6) and its downstream effector ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 (AMAP1) drive cancer invasion, metastasis, and therapy resistance. The Arf6-AMAP1 pathway has been reported to promote receptor recycling leading to programmed cell death-ligand 1 (PD-L1) overexpression in pancreatic ductal carcinoma. Moreover, AMAP1 regulates of nuclear factor-kappa B (NF-κB), which is an important molecule in inflammation and immune activation, including tumor immune interaction through PD-L1 regulation. In this study, we investigated the function of AMAP1 on PD-L1 expression using lung cancer cells.Methods: We used two non-small cell lung cancer cell lines. Protein expression was evaluated by Western blotting. AMAP1 and NF-kB expression were reduced by conventional siRNA methods, and osimertinib was used as an epithelial growth factor receptor (EGFR) inhibitor. Multiple analysis of receptor tyrosine kinases (RTKs) was conducted using a semi-comprehensive RTKs assay.Results: We found that AMAP1 inversely regulated PD-L1 expression. Based on these results, we examined the activation levels of RTKs associated with both AMAP1 and PD-L1. Following a semi-comprehensive phosphorylated RTK assay, we observed the upregulation of phosphorylated EGFR (pEGFR) led by the downregulation of AMAP1. The inhibition of pEGFR by osimertinib downregulates PD-L1 expression. We investigated the relationships between AMAP1, NF-κB, and PD-L1 expression. AMAP1 knockdown upregulated the expression of both NF-κB and PD-L1. Subsequently, NF-κB knockdown downregulated PD-L1 levels, while double knockdown of AMAP1 and NF-κB, restored PD-L1 expression.Conclusion: AMAP1 may inversely regulate PD-L1 through negative feedback of pEGFR and activation of NF-κB in NSCLC cell lines.Keywords: AMAP1, PD-L1, NF-κB, pEGFRhttps://www.dovepress.com/arfgap-with-the-sh3-domain-ankyrin-repeat-and-ph-domain-1-inversely-re-peer-reviewed-fulltext-article-CMARamap1pd-l1nf-κbpegfr |
| spellingShingle | Chiba N Menju T Shimazu Y Toyazaki T Sumitomo R Miyamoto H Tamari S Nishikawa S Date H ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 Inversely Regulates Programmed Death-Ligand 1 Through Negative Feedback of Phosphorylated Epithelial Growth Factor Receptor and Activation of Nuclear Factor-Kappa B in Non-Small Cell Lung Cancer Cancer Management and Research amap1 pd-l1 nf-κb pegfr |
| title | ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 Inversely Regulates Programmed Death-Ligand 1 Through Negative Feedback of Phosphorylated Epithelial Growth Factor Receptor and Activation of Nuclear Factor-Kappa B in Non-Small Cell Lung Cancer |
| title_full | ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 Inversely Regulates Programmed Death-Ligand 1 Through Negative Feedback of Phosphorylated Epithelial Growth Factor Receptor and Activation of Nuclear Factor-Kappa B in Non-Small Cell Lung Cancer |
| title_fullStr | ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 Inversely Regulates Programmed Death-Ligand 1 Through Negative Feedback of Phosphorylated Epithelial Growth Factor Receptor and Activation of Nuclear Factor-Kappa B in Non-Small Cell Lung Cancer |
| title_full_unstemmed | ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 Inversely Regulates Programmed Death-Ligand 1 Through Negative Feedback of Phosphorylated Epithelial Growth Factor Receptor and Activation of Nuclear Factor-Kappa B in Non-Small Cell Lung Cancer |
| title_short | ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 Inversely Regulates Programmed Death-Ligand 1 Through Negative Feedback of Phosphorylated Epithelial Growth Factor Receptor and Activation of Nuclear Factor-Kappa B in Non-Small Cell Lung Cancer |
| title_sort | arfgap with the sh3 domain ankyrin repeat and ph domain 1 inversely regulates programmed death ligand 1 through negative feedback of phosphorylated epithelial growth factor receptor and activation of nuclear factor kappa b in non small cell lung cancer |
| topic | amap1 pd-l1 nf-κb pegfr |
| url | https://www.dovepress.com/arfgap-with-the-sh3-domain-ankyrin-repeat-and-ph-domain-1-inversely-re-peer-reviewed-fulltext-article-CMAR |
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