| Project/Area Number |
16K09399
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
Michihiro Ono 札幌医科大学, 医学部, 助教 (80634675)
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| Co-Investigator(Kenkyū-buntansha) |
宮西 浩嗣 札幌医科大学, 医学部, 准教授 (60372819)
菊地 尚平 札幌医科大学, 医学部, 助教 (80515792)
加藤 淳二 札幌医科大学, 医学部, 教授 (20244345)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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| Keywords | HDAC阻害剤 / 膵癌 / 細胞周期停止 / 細胞周期 / FOXO3a / エピジェネティクス / 膵がん / ● |
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| Outline of Final Research Achievements |
Pancreatic cancer is highly chemo-resistant associated with oncogenic mutations such as KRAS and/or p53. Selective class IIa HDAC inhibitor TMP269 treatment showed increased FoxO3a expression in a dose dependent manner with immunoblotting and modest cell growth inhibition effect at 57.5 μM of IC50 dose for 48-hour treatment against AsPC-1 in MTT. G1/S arrest was observed with cell cycle assay. Upregulated p21Waf1/Cip1 and downregulated CDK2 and 4/6 and cyclin D1 and D2 expressions were further observed, consistent with inducing G1/S arrest and transcriptionally activated FoxO3a. Importantly, upregulated p21Waf1/Cip1 was observed in AsPC-1 p53 null cell line, suggesting independent with p53 pathway. These findings suggest upregulated FoxO3a induced by HDAC class IIa inhibition activated its transcription and resulted in cell growth inhibition.
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| Academic Significance and Societal Importance of the Research Achievements |
通常の化学療法剤では極めて難治性の膵癌診療において、選択的HDAC class IIa 阻害剤が細胞増殖抑制効果を示し、新規治療戦略の可能性を示した。特にp53やRASなど、遺伝子異常が通常の化学療法剤の治療抵抗性に関与しているが、TMP269がp53欠損株においても、p53非依存性にp21の発現増強を介して、細胞増殖抑制効果を示しており、治療抵抗性の克服に対しても、可能性を示した。
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