M-COPA, a novel Golgi system disruptor, suppresses apoptosis induced by Shiga toxin.
Shiga toxin (Stx) is a main virulence factor of Stx-producing Escherichia coli (STEC) that contributes to diarrhea and hemorrhagic colitis and occasionally to fatal systemic complications. Therefore, the development of an antidote to neutralize Stx toxicity is urgently needed. After internalization into cells, Stx is transferred to the Golgi apparatus via a retrograde vesicular transport system. We report here that 2-methylcoprophilinamide (M-COPA), a compound that induces disassembly of the Golgi apparatus by inactivating ADP-ribosylation factor 1 (Arf1), suppresses Stx-induced apoptosis. M-COPA inhibited transport of Stx from the plasma membrane to the Golgi apparatus and suppressed degradation of anti-apoptotic proteins and the activation of caspases. These findings suggest that inhibition of Stx retrograde transport by M-COPA could be a novel approach to suppress Stx toxicity.
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
Takayuki
T
Hattori
Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakotani, Tatara, Kyotanabe, Kyoto, 610-0394, Japan.
Miho
M
Watanabe-Takahashi
Department of Applied Chemistry, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan.
Isamu
I
Shiina
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
Yoshimi
Y
Ohashi
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
Shingo
S
Dan
Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakotani, Tatara, Kyotanabe, Kyoto, 610-0394, Japan.
Kiyotaka
K
Nishikawa
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.|Center for Product Evaluation, Pharmaceuticals and Medical Device Agency, Shin-Kasumigaseki Building 3-3-2 Kasumigaseki, Tokyo, 100-0013, Japan.
Takao
T
Yamori
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
Mikihiko
M
Naito
D020823:ADP-Ribosylation Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D000931:Antidotes / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D003092:Colitis / Q000188:drug therapy / Q000382:microbiology; D003967:Diarrhea / Q000188:drug therapy / Q000382:microbiology; D006056:Golgi Apparatus / Q000187:drug effects; D006801:Humans; D009284:Naphthols / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D022621:Shiga Toxin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D054323:Shiga-Toxigenic Escherichia coli / Q000187:drug effects* / Q000472:pathogenicity
D000475:Alkenes; D000931:Antidotes; C573938:N-(pyridine-3-ylmethyl)-5-(7-hydroxy-2,6,8-trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-yl)-2-methylpenta-2,4-dienamide; D009284:Naphthols; D011725:Pyridines; C117996:coprophilin; D022621:Shiga Toxin; D020823:ADP-Ribosylation Factor 1