2018 Fiscal Year Final Research Report

Molecular mechanisms and roles of pyroptosis

Planned Research

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Project Area	Homeostatic Regulation by Various Types of Cell Death
Project/Area Number	26110002
Research Category	Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
Allocation Type	Single-year Grants
Review Section	Biological Sciences
Research Institution	Kanazawa University
Principal Investigator	Suda Takashi 金沢大学, がん進展制御研究所, 教授 (70250090)
Research Collaborator	Suzuki Yutaka Kinoshita Takeshi Tsuchiya Kosuke Nakajima Shinsuke
Project Period (FY)	2014-07-10 – 2019-03-31
Keywords	パイロトーシス / アポトーシス / カスパーゼ-1 / がん治療 / がん免疫
Outline of Final Research Achievements	This study aimed to clarify molecular mechanisms and roles of caspase-1-meidated cell death. Recent studies identified gasdermin D (GSDMD) as the effector molecule of pyroptosis, a caspase-1-dependent inflammatory cell death. However, GSDMD-deficient macrophages are still susceptible to caspase-1 activation. Thus, we investigated the molecular mechanism of caspase-1-dependent GSDMD-independent cell death. We found that GSDMD-deficient cells exhibits Bid-dependent apoptosis in response to caspase-1 activation. We found the same for inherently GSDMD-null/low cells such as neuronal cells and mast cells. These findings may contribute to understanding of the mechanism of caspase-1-related diseases such as neurodegenerative diseases. In addition, we demonstrated that pyroptotic cell death of tumor cells induces stronger anti-tumor immune responses than apoptotic cell death in an animal tumor therapy model. The latter finding may help to develop novel strategy of cancer therapy.
Free Research Field	分子生物学、免疫学、腫瘍生物学
Academic Significance and Societal Importance of the Research Achievements	カスパーゼ1はアルツハイマー病、虚血性脳傷害、筋委縮性側索硬化症などの神経変性疾患をはじめ、虚血性心疾患や腎疾患などで細胞死に関与するとの報告がある。カスパーゼ1依存性細胞死に関する我々の成果はこれらの疾患の発症機序の解明に寄与する可能性がある。また、最近、がん免疫療法の有効性が注目されており、がん細胞にパイロトーシスを誘導した方がアポトーシスを誘導するより、強く抗腫瘍免疫を活性化するという我々の発見は、がん治療の新しい指針の一つとなる可能性がある。