Mechanism of Shiga toxin-induced cell death and development of therapeutic agent

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K08040
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: National Institute of Health Sciences
• Principal Investigator: HATTORI TAKAYUKI 国立医薬品食品衛生研究所, 遺伝子医薬部, 主任研究官 (50377751)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 志賀毒素 / THP1細胞 / アポトーシス / プロテアソーム / 小胞輸送阻害 / 耐性 / CD77 / CD77 synthase

Outline of Final Research Achievements

Shiga toxin (Stx) causes fatal systemic complications. Stx induces apoptosis, but the mechanism of which is unclear. Therefore, the development of an antidote to neutralize Stx toxicity is urgently required. Proteasome inhibitors prevented the induction of apoptosis in vitro. A clinically approved proteasome inhibitor, bortezomib, improved the survival rate of mice challenged by Stx.
We also demonstrated that AMF26, a compound that induces disassembly of the Golgi apparatus by inactivating ADP-ribosylation factor 1, suppresses Stx-induced apoptosis in vitro.
Furthermore, we isolated resistant clones to Stx-induced cell death from THP1 cells. The resistant clones lost the expression of CD77 as a consequence of the reduction in CD77 synthase mRNA expression. The result suggests that downregulation of CD77 or CD77 synthase expression could be a novel approach to neutralize the fatal toxicity of Stx.

Free Research Field

分子生物学、生化学、細胞生物学