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...
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2017
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oai:doaj.org-article:f5cdc61bc8ea4f0a8fc5652c9651c68c2021-12-02T11:52:44ZInhibitory effects of local anesthetics on the proteasome and their biological actions10.1038/s41598-017-04652-22045-2322https://doaj.org/article/f5cdc61bc8ea4f0a8fc5652c9651c68c2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04652-2https://doaj.org/toc/2045-2322Abstract 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.Udin BahrudinMasaki UnnoKazuya NishioAkiko KitaPeili LiMasaru KatoMasashi InoueShunichi TsujitaniTakuto MurakamiRina SugiyamaYasushi SaekiYuji ObaraKeiji TanakaHiroshi YamaguchiIsao SakaneYasushi KawataToshiyuki ItohHaruaki NinomiyaIchiro HisatomeYukio MorimotoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017) |
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Medicine R Science Q 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 |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
inhibitory effects of local anesthetics on the proteasome and their biological actions |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/f5cdc61bc8ea4f0a8fc5652c9651c68c |
| work_keys_str_mv |
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| _version_ |
1718394961538318336 |