2021 Fiscal Year Final Research Report
Metabolic mechanism for transcriptional induction of chronic inflammation
Project/Area Number |
19K07887
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 52010:General internal medicine-related
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Research Institution | Kyoto University |
Principal Investigator |
MIKAWA Takumi 京都大学, 医学研究科, 研究員 (90608051)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Keywords | 解糖系酵素 / 発癌 / PGAM |
Outline of Final Research Achievements |
The purpose of this research was to "elucidate the metabolic molecular mechanism of chronic inflammation linked to aging and age-related diseases." Especially, we analyzed the glycolytic control mechanism by glycolytic metabolic enzyme PGAM and focused on the involvement of PGAM in inflammation and tumor growth, which is one of the age-related diseases. We identified that PGAM plays a key role in regulating glycolysis in cancer cells, but not in standard cells. Cancer-prone phenotype by PGAM-overexpression in vivo were associated with upregulated glycolytic features. PGAM interacts and cooperates with Chk1 to regulate the enhanced glycolysis in cancer cells, especially under oncogenic Ras expressing conditions. Genetic interference of the PGAM-Chk1 interaction, with intact PGAM activity, abrogated the maintenance of cancerous enhanced glycolysis. Thus, the nonenzymatic function of PGAM is essential for the Warburg effect that accompanies cancerous proliferation.
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Free Research Field |
老年医学
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Academic Significance and Societal Importance of the Research Achievements |
これまでの解糖系阻害を標的とした抗癌剤開発は、酵素活性阻害剤がその主流であったため、正常細胞の解糖系も阻害し、その結果、甚大な副作用により実用化できていなかった。今回の我々の見出した「PGAMの非酵素活性」をターゲットとすることで、正常細胞の解糖系にはより影響の少ない形で、癌細胞のワールブルグ効果に対する阻害剤の開発が期待できる。
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