Inhibitory effects of local anesthetics on the proteasome and their biological actions

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Authors	Bahrudin, Udin Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University / Present address: Department of Cardiology and Vascular Medicine, Faculty of Medicine, Diponegoro University Unno, Masaki Graduate School of Science and Engineering, Ibaraki University / Frontier Research Center for Applied Atomic Sciences, Ibaraki University Nishio, Kazuya Research Reactor Institute, Kyoto University / Present address: Graduate School of Life Science, University of Hyogo Kita, Akiko Research Reactor Institute, Kyoto University Li, Peili Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University Researchers DB KAKEN Kato, Masaru Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University Researchers DB KAKEN Inoue, Masashi Department of Surgery, National Hospital Organization Kure Medical Center Tsujitani, Shunichi Cancer Center, Tottori University Hospital Murakami, Takuto School of Science and Technology, Kwansei Gakuin University / RIKEN SPring-8 Center, RIKEN Harima Institute Sugiyama, Rina Graduate School of Science and Engineering, Ibaraki University Saeki, Yasushi Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science Obara, Yuji Graduate School of Science and Engineering, Ibaraki University / Frontier Research Center for Applied Atomic Sciences, Ibaraki University Tanaka, Keiji Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science Yamaguchi, Hiroshi School of Science and Technology, Kwansei Gakuin University / RIKEN SPring-8 Center, RIKEN Harima Institute Sakane, Isao Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University Kawata, Yasushi Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University Researchers DB KAKEN Itoh, Toshiyuki Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University Researchers DB KAKEN Ninomiya, Haruaki Department of Biological Regulation, Tottori University Researchers DB KAKEN Hisatome, Ichiro Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University Researchers DB KAKEN Morimoto, Yukio Research Reactor Institute, Kyoto University
Keywords	Kososan Recurrent depression Social defeat stress Antidepressant
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.
Publisher	Springer Nature
Content Type	Journal Article
Link	https://www.nature.com/articles/s41598-017-04652-2
ISSN	20452322
Journal Title	SCIENTIFIC REPORTS
Current Journal Title	SCIENTIFIC REPORTS
Volume	7
Published Date	2017-07-11
Publisher-DOI	10.1038/s41598-017-04652-2
Text Version	Publisher
Rights	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Citation	Bahrudin Udin, Unno Masaki, Nishio Kazuya, et al. Inhibitory effects of local anesthetics on the proteasome and their biological actions. SCIENTIFIC REPORTS. 2017. 7. doi:10.1038/s41598-017-04652-2
Department	Faculty of Medicine/Graduate School of Medical Sciences/University Hospital
Language	English
Web of Science Key ut	WOS:000405172600046