Cell death induced by arsenite in relation to autophasy and proteasome system

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09201
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Legal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: UEMURA Koichi 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30244586)
• Co-Investigator(Kenkyū-buntansha): 秋 利彦 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (60304474) ; 船越 丈司 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (40444715)
• Research Collaborator: WATANABE Ryo
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ヒ素 / 脳 / PML / ATR-Chk経路

Outline of Final Research Achievements

The purpose of this study is to clarify arsenic trioxide (ATO) induced organ damag by the administration of ATO to rat or cultured cells, in relation to cell death related proteins or death signal pathway. We clarified DNA damage occurred in the brain where ATO was administrated after 48hrs and DNA damadge checkpoint AR-Chk pathway was activated with PML (promyelocytic leukemia protein)
upregulation. This is because DNA damage was restored and apoptosis did not occur, while in the cultured SH-SY5Y cells, apoptosis was not preventable in spite of phosphorylation of Chk1. After the ATO administration to rat, DNA damage occurred relatively in the early stage with the PML upreguration.

Free Research Field

法医学

Academic Significance and Societal Importance of the Research Achievements

中毒物質として重要なヒ素を取り上げ、ヒ素の各臓器に対する障害作用の機構の解明を目的とする。ヒ素は急性前骨髄性白血病の治療薬として用いられ、ヒ素の細胞への作用機序の詳細の解明によって、副作用の少ない抗癌剤の開発にも資する。ラット脳組織ではヒ素が起こすDNA損傷に対してATR-Chk経路だけでなく、PMLも変動し、細胞死を抑制していた。一方、神経系培養細胞ではChk1のリン酸化を認めたが、細胞死をを防げなかった。ヒ素の作用機序の一部が解明された。