Inhibitory effects of local anesthetics on the proteasome and their biological actions
Abstract Local anesthetics (LAs) inhibit endoplasmic reticulum-associated protein degradation, however the mechanisms remain elusive. Here, we show that the clinically used LAs pilsicainide and lidocaine bind directly to the 20S proteasome and inhibit its activity. Molecular dynamic calculation indi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-04652-2 |
| _version_ | 1818429033293021184 |
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| author | Udin Bahrudin Masaki Unno Kazuya Nishio Akiko Kita Peili Li Masaru Kato Masashi Inoue Shunichi Tsujitani Takuto Murakami Rina Sugiyama Yasushi Saeki Yuji Obara Keiji Tanaka Hiroshi Yamaguchi Isao Sakane Yasushi Kawata Toshiyuki Itoh Haruaki Ninomiya Ichiro Hisatome Yukio Morimoto |
| author_facet | Udin Bahrudin Masaki Unno Kazuya Nishio Akiko Kita Peili Li Masaru Kato Masashi Inoue Shunichi Tsujitani Takuto Murakami Rina Sugiyama Yasushi Saeki Yuji Obara Keiji Tanaka Hiroshi Yamaguchi Isao Sakane Yasushi Kawata Toshiyuki Itoh Haruaki Ninomiya Ichiro Hisatome Yukio Morimoto |
| author_sort | Udin Bahrudin |
| collection | DOAJ |
| description | Abstract Local anesthetics (LAs) inhibit endoplasmic reticulum-associated protein degradation, however the mechanisms remain elusive. Here, we show that the clinically used LAs pilsicainide and lidocaine bind directly to the 20S proteasome and inhibit its activity. Molecular dynamic calculation indicated that these LAs were bound to the β5 subunit of the 20S proteasome, and not to the other active subunits, β1 and β2. Consistently, pilsicainide inhibited only chymotrypsin-like activity, whereas it did not inhibit the caspase-like and trypsin-like activities. In addition, we confirmed that the aromatic ring of these LAs was critical for inhibiting the proteasome. These LAs stabilized p53 and suppressed proliferation of p53-positive but not of p53-negative cancer cells. |
| first_indexed | 2024-12-14T15:11:05Z |
| format | Article |
| id | doaj.art-f5cdc61bc8ea4f0a8fc5652c9651c68c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T15:11:05Z |
| publishDate | 2017-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-f5cdc61bc8ea4f0a8fc5652c9651c68c2022-12-21T22:56:33ZengNature PortfolioScientific Reports2045-23222017-07-01711910.1038/s41598-017-04652-2Inhibitory effects of local anesthetics on the proteasome and their biological actionsUdin Bahrudin0Masaki Unno1Kazuya Nishio2Akiko Kita3Peili Li4Masaru Kato5Masashi Inoue6Shunichi Tsujitani7Takuto Murakami8Rina Sugiyama9Yasushi Saeki10Yuji Obara11Keiji Tanaka12Hiroshi Yamaguchi13Isao Sakane14Yasushi Kawata15Toshiyuki Itoh16Haruaki Ninomiya17Ichiro Hisatome18Yukio Morimoto19Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori UniversityGraduate School of Science and Engineering, Ibaraki UniversityResearch Reactor Institute, Kyoto UniversityResearch Reactor Institute, Kyoto UniversityInstitute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori UniversityDepartment of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori UniversityDepartment of Surgery, National Hospital Organization Kure Medical CenterCancer Center, Tottori University HospitalSchool of Science and Technology, Kwansei Gakuin UniversityGraduate School of Science and Engineering, Ibaraki UniversityLaboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical ScienceGraduate School of Science and Engineering, Ibaraki UniversityLaboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical ScienceSchool of Science and Technology, Kwansei Gakuin UniversityDepartment of Chemistry and Biotechnology, Graduate School of Engineering, Tottori UniversityDepartment of Chemistry and Biotechnology, Graduate School of Engineering, Tottori UniversityDepartment of Chemistry and Biotechnology, Graduate School of Engineering, Tottori UniversityDepartment of Biological Regulation, Tottori UniversityInstitute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori UniversityResearch Reactor Institute, Kyoto UniversityAbstract Local anesthetics (LAs) inhibit endoplasmic reticulum-associated protein degradation, however the mechanisms remain elusive. Here, we show that the clinically used LAs pilsicainide and lidocaine bind directly to the 20S proteasome and inhibit its activity. Molecular dynamic calculation indicated that these LAs were bound to the β5 subunit of the 20S proteasome, and not to the other active subunits, β1 and β2. Consistently, pilsicainide inhibited only chymotrypsin-like activity, whereas it did not inhibit the caspase-like and trypsin-like activities. In addition, we confirmed that the aromatic ring of these LAs was critical for inhibiting the proteasome. These LAs stabilized p53 and suppressed proliferation of p53-positive but not of p53-negative cancer cells.https://doi.org/10.1038/s41598-017-04652-2 |
| spellingShingle | Udin Bahrudin Masaki Unno Kazuya Nishio Akiko Kita Peili Li Masaru Kato Masashi Inoue Shunichi Tsujitani Takuto Murakami Rina Sugiyama Yasushi Saeki Yuji Obara Keiji Tanaka Hiroshi Yamaguchi Isao Sakane Yasushi Kawata Toshiyuki Itoh Haruaki Ninomiya Ichiro Hisatome Yukio Morimoto Inhibitory effects of local anesthetics on the proteasome and their biological actions Scientific Reports |
| title | Inhibitory effects of local anesthetics on the proteasome and their biological actions |
| title_full | Inhibitory effects of local anesthetics on the proteasome and their biological actions |
| title_fullStr | Inhibitory effects of local anesthetics on the proteasome and their biological actions |
| title_full_unstemmed | Inhibitory effects of local anesthetics on the proteasome and their biological actions |
| title_short | Inhibitory effects of local anesthetics on the proteasome and their biological actions |
| title_sort | inhibitory effects of local anesthetics on the proteasome and their biological actions |
| url | https://doi.org/10.1038/s41598-017-04652-2 |
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