Expression of a 10-formyltetrahydorofolate-metabolizing enzyme affects mitochondrial respiration and 5-aminoimidazole-4-carboxamide ribonucleoside sensitivity

<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>