Proteasome inhibitors prevent cell death and prolong survival of mice challenged by Shiga toxin

• Shiga toxin (Stx) rapidly reduces the level of short-lived anti-apoptotic proteins.
• Stx induces activation of caspase 9 and apoptosis.
• Proteasome inhibitors prevent the reduction of anti-apoptotic proteins.
• Proteasome inhibitors suppress Stx-induced apoptosis.
• Bortezomib prolongs the survival of mice challenged with a lethal dose of Stx.

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.