2023 Fiscal Year Final Research Report
RB1 tumor suppressor functions in metabolism
| Project/Area Number |
20H03509
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | がん抑制遺伝子 / がん代謝 / 解糖系 / ミトコンドリア / 脂質代謝 / RB1 |
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| Outline of Final Research Achievements |
We found that the RB1-PGAM axis positively controls muscle differentiation. Inhibition of the RB1 downstream gene ELOVL6 in breast cancer showed growth suppression. We found that ceramide production increases following ELOVL6 inhibition, which suppresses AKT signaling. We elucidated the action of cholesterol as a fate metabolite regulated by RB1. We found a mechanism whereby the regulation of the isoprenylation pathway by RB1 is compensated for by p130. We found that early resistance of RB1 wild-type hepatocellular carcinoma to CDK4/6 inhibitors depends on IKKb-NF-kB and AKT activity. We explored rationales for adaptation of CDK4/6 inhibitor combination therapy recipe for KRAS mutant pancreatic cancer.
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| Free Research Field |
腫瘍学
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| Academic Significance and Societal Importance of the Research Achievements |
RB1不活性化は、発がん時よりもむしろ悪性進展時において頻繁である。この帰結は、未分化性・薬剤耐性誘導、腫瘍微小環境の改編や代謝リプログラミングなど、従来知られた細胞周期制御の破綻では説明できない事象群である。本研究は、細胞内の代謝制御におけるRB1機能に焦点を当て、解糖系、脂質合成系、コレステロール合成、脂肪酸酸化、核酸代謝系において特異的なRB1標的を見出し、この生物学的・臨床的意義を探索した。このような非古典的なRB1標的のなかには、新規がん治療標的として有望な分子が含まれるかもしれない。
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