| Project/Area Number |
18KK0445
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| Research Category |
Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
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| Allocation Type | Multi-year Fund |
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| Research Field |
Experimental pathology
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| Research Institution | Kagawa University (2021)
Hokkaido University (2018-2020) |
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Principal Investigator |
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| Project Period (FY) |
2019 – 2021
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
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| Keywords | Pin1 / リソソーム / タンパク分解 / HIP1R / 膵癌 / オートファジー / 生体膜動態 / 形態形成 / Akt / 細胞膜リン脂質 |
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| Outline of Final Research Achievements |
Prolyl isomerase Pin1 has been shown to play an important role in the formation of early endosomes and LC3 puncta which observed during autophagosome formation as one of the regulation of plasma membrane phospholipid dynamics.
Pin1 cooperates with the clathrin-dependent endocytosis regulator HIP1R to lysosome-dependently degrade PD-L1 which is a target factor of cancer immunity and ENT1 which is a nucleic acid transporter. Regulation of the degradation of major cancer-related factors by Pin1 affects not only tumor cells, but also cancer-related fibroblasts (CAFs) that form cancer-supporting stroma tissues in the cancer microenvironment, and treatment and treatment with CAF which is affecting drug resistance of tumor.
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| Academic Significance and Societal Importance of the Research Achievements |
Pin1は、様々ながん腫において強発現しており、細胞周期制御因子や炎症制御プロセスに重要な役割を果たすプロリル異性化酵素である。現在までにPin1は、数十種のがん遺伝子産物の発現誘導や活性化、さらには、がん抑制遺伝子の発現抑制や不活性化のプロセスに関わる事が明らかになっており、癌治療標的因子として注目されている。今回の共同研究において、Pin1阻害剤、がん免疫活性化PD-L1抗体、抗がん剤Gemcitabineの併用により細胞レベル、自然発生膵癌マウスモデルで副作用を低減しかつ劇的な抗がん作用相乗効果がみられたことから、今後本ストラテジーによる臨床応用への展開が期待できる。
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