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

被引：3

作者：

Bahrudin, Udin ^{[1
,13
]}

Unno, Masaki ^{[2
,3
]}

Nishio, Kazuya ^{[4
,14
]}

Kita, Akiko ^{[4
]}

Li, Peili ^{[1
]}

Kato, Masaru ^{[5
]}

Inoue, Masashi ^{[6
]}

Tsujitani, Shunichi ^{[7
]}

Murakami, Takuto ^{[8
,9
]}

Sugiyama, Rina ^{[2
]}

Saeki, Yasushi ^{[10
]}

Obara, Yuji ^{[2
,3
]}

Tanaka, Keiji ^{[10
]}

Yamaguchi, Hiroshi ^{[8
,9
]}

Sakane, Isao ^{[11
]}

Kawata, Yasushi ^{[11
]}

Itoh, Toshiyuki ^{[11
]}

Ninomiya, Haruaki ^{[12
]}

Hisatome, Ichiro ^{[1
]}

Morimoto, Yukio ^{[4
]}

机构：

[1] Tottori Univ, Grad Sch Med Sci, Inst Regenerat Med & Biofunct, Yonago, Tottori, Japan

[2] Ibaraki Univ, Grad Sch Sci & Engn, Hitachi, Ibaraki, Japan

[3] Ibaraki Univ, Frontier Res Ctr Appl Atom Sci, Tokai, Ibaraki, Japan

[4] Kyoto Univ, Inst Res Reactor, Kumatori, Osaka, Japan

[5] Tottori Univ, Dept Mol Med & Therapeut, Fac Med, Yonago, Tottori, Japan

[6] Natl Hosp Org, Kure Med Ctr, Dept Surg, Hiroshima, Japan

[7] Tottori Univ Hosp, Canc Ctr, Yonago, Tottori, Japan

[8] Kwansei Gakuin Univ, Sch Sci & Technol, Sanda, Hyogo, Japan

[9] RIKEN Harima Inst, RIKEN SPring Ctr 8, Sayo, Hyogo, Japan

[10] Tokyo Metropolitan Inst Med Sci, Lab Prot Metab, Tokyo, Japan

[11] Tottori Univ, Grad Sch Engn, Dept Chem & Biotechnol, Tottori, Japan

[12] Tottori Univ, Dept Biol Regulat, Yonago, Tottori, Japan

[13] Diponegoro Univ, Fac Med, Dept Cardiol & Vasc Med, Semarang, Central Java, Indonesia

[14] Univ Hyogo, Grad Sch Life Sci, Kamigori, Hyogo, Japan

来源：

SCIENTIFIC REPORTS | 2017年 / 7卷

关键词：

20; S-PROTEASOME; CHANNEL PROTEIN; DEGRADATION; DOCKING; CONNEXIN43; PEPTIDES; MUTATION; MODEL; SCN5A; P53;

D O I：

10.1038/s41598-017-04652-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta 5 subunit of the 20S proteasome, and not to the other active subunits, beta 1 and beta 2. 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 p53positive but not of p53-negative cancer cells.

引用

页数：9

共 42 条

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