Toward a Complete Elucidation of the Cancer Suppressive Function of Aldehyde Dehydrogenase Involved in Folic Acid Metabolism

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K05731
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: Tohoku Medical and Pharmaceutical University
• Principal Investigator: Sasaki Masato 東北医科薬科大学, 薬学部, 准教授 (30396527)
• Co-Investigator(Kenkyū-buntansha): 山本 一男 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (70255123)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: がん代謝 / de novo ヌクレオチド合成 / 翻訳後修飾 / ユビキチン

Outline of Final Research Achievements

Using ALDH1L1 stably expressing HuH-7 cells, metabolomic analysis revealed a decrease in Ser and an increase in Gly and an increase in ZMP, de novo purine nucleotide synthesis intermediate ZMP. Although ZMP is an activator of endogenous AMPK, ZMP derived from ALDH1L1 expression had no effect on AMPK activity. On the other hand, ZMP causes a decrease in mitochondrial membrane potential, but ALDH1L1 expression was resistant to a decrease in mitochondrial membrane potential. Database analysis showed that high and low expression of ALDH1L1 differentially expressed genes involved in oxidative phosphorylation and fatty acid metabolism, and that a group of liver cancer cell lines with low ALDH1L1 expression were sensitive to ZMP and cordycepin. We also found that ALDH1L1 expression did not affect de novo pyrimidine nucleotide synthesis or the salvage pathway. These were submitted as two papers and accepted.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

がん抑制遺伝子として推定されているALDH1L1遺伝子の肝臓がんにおける役割の一端を明らかとしたことで、肝臓がんにおける葉酸代謝の重要性をあらためて示すことができた。肝臓がんではALDH1L1発現が低下していることが多いが、ALDH1L1の役割が明らかとなったことで、新たな治療標的の策定が可能になると予想される。また、既存の核酸アナログに対する感受性試験の結果から、ALDH1L1発現の高低にかかわらず、これらの治療薬に有効であることが示された。以上の発見が、今後の肝臓がん治療の選択肢の幅を広げることにつながることが期待される。