Proteasome inhibitors prevent cell death and prolong survival of mice challenged by Shiga toxin.
Shiga toxin (Stx) causes fatal systemic complications. Stx induces apoptosis, but the mechanism of which is unclear. We report that Stx induced rapid reduction of short-lived anti-apoptotic proteins followed by activation of caspase 9 and the progression of apoptosis. Proteasome inhibitors prevented the reduction of anti-apoptotic proteins, and inhibited caspase activation and apoptosis, suggesting that the reduction of anti-apoptotic proteins is a prerequisite for Stx-induced apoptosis. A clinically approved proteasome inhibitor, bortezomib, prolonged the survival of mice challenged by Stx. These results imply that proteasome inhibition may be a novel approach to prevent the fatal effects of Stx.
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Tokyo 158-8501, Japan.
Takayuki
T
Hattori
Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0394, Japan.
Miho
M
Watanabe-Takahashi
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Tokyo 158-8501, Japan.
Nobumichi
N
Ohoka
Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
Takashi
T
Hamabata
Department of Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya 466-0065, Japan.
Koichi
K
Furukawa
Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0394, Japan.
Kiyotaka
K
Nishikawa
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Tokyo 158-8501, Japan.
Mikihiko
M
Naito
Apoptosis; Apoptosis inhibitory proteins; BRZ, bortezomib; CHX, cycloheximide; ER, endoplasmic reticulum; FLIP, FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein; Mcl-1, myeloid cell leukemia 1; PARP, Poly(ADP-ribose) polymerase; PI, propidium iodide; Proteasome; Proteasome inhibitor; STEC, Shiga toxin-producing Escherichia coli; Shiga toxin; Stx, Shiga toxin; c-IAP1, cellular inhibitor of apoptosis protein 1