Expression of a 10-formyltetrahydorofolate-metabolizing enzyme affects mitochondrial respiration and 5-aminoimidazole-4-carboxamide ribonucleoside sensitivity
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- SASAKI Masato
- Tohoku Medical and Pharmaceutical Univ.
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- YAMAMOTO Kazuo
- Nagasaki Univ.
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- UEDA Takeshi
- Kindai Univ.
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- IROKAWA Hayato
- Tohoku Medical and Pharmaceutical Univ.
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- TAKEDA Kouki
- Tohoku Medical and Pharmaceutical Univ.
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- SEKINE Ryoya
- Tohoku Medical and Pharmaceutical Univ.
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- ITO Fumie
- Tohoku Medical and Pharmaceutical Univ.
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- TANAKA Yutaka
- Tohoku Medical and Pharmaceutical Univ.
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- KUGE Shusuke
- Tohoku Medical and Pharmaceutical Univ.
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- SHIBATA Nobuyuki
- Tohoku Medical and Pharmaceutical Univ.
Bibliographic Information
- Other Title
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- 10-ホルミルテトラヒドロ葉酸代謝酵素の発現はミトコンドリア活性と5-アミノイミダゾール-4-カルボキサミドリボヌクレオシド感受性に影響を及ぼす
Abstract
<p>One-carbon metabolism is utilized for the de novo synthesis of purines, thymidylate, mitochondrial formylmethionyl-tRNA, and S-adenosylmethionine. Given that tumor cells require large amounts of nucleotides, they are highly dependent on one-carbon metabolism. Consequently, anti-folate agents have been utilized for tumor therapy. Among the one-carbon-metabolizing enzymes, the aldehyde dehydrogenase 1 family member L1 (ALDH1L1), which catalyzes 10-formyltetrahydrofolate (10-fTHF) to THF, is considered a tumor suppressor gene, as its expression is reported to be attenuated or diminished in hepatocellular carcinoma (HCC). Recently, we found that 5-aminoimidazole-4-carboxamide ribonucleotide (ZMP), an intermediate in de novo purine synthesis, accumulates in the HuH7 cell line stably expressing ALDH1L1, as a consequence of impaired reception of a formyl group from 10-fTHF. Furthermore, there were reductions in intracellular serine levels in ALDH1L1-expressing cells, which, in turn, may influence mitochondrial serine catabolism linked to THF metabolism. In response to these metabolic changes, energy production via the electron transport chain is restricted. Furthermore, ALDH1L1-expressing cells are resistant to 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), which is the nucleoside form of ZMP. Although AICAr causes cell cycle arrest, regardless of ALDH1L1 expression, ALDH1L1-expressing cells maintained mitochondrial basal respiration. Collectively, these findings indicate that AICAr could be effective in the pharmacotherapy of HCC patients with a low expression of ALDH1L1.</p>
Journal
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- Annual Meeting of the Japanese Society of Toxicology
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Annual Meeting of the Japanese Society of Toxicology 50.1 (0), O3-37-, 2023
The Japanese Society of Toxicology
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Details 詳細情報について
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- CRID
- 1390580870561219712
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- Text Lang
- ja
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- Data Source
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- JaLC
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- Abstract License Flag
- Disallowed