RRC ID 59959
著者 Shidoji Y, Tabata Y.
タイトル Unequivocal evidence for endogenous geranylgeranoic acid biosynthesized from mevalonate in mammalian cells.
ジャーナル J Lipid Res
Abstract Geranylgeranoic acid (GGA) has been reported to induce autophagic cell death via upregulation of lipid-induced unfolded protein response in several human hepatoma-derived cell lines, and its 4,5-didehydro derivative has been developed as a preventive agent against second primary hepatoma in clinical trials. We have previously reported that GGA is a natural diterpenoid synthesized in several medicinal herbs. Here, we provide unequivocal evidence for de novo GGA biosynthesis in mammals. First, with normal male Wistar rats, the levels of GGA in liver were found to be far greater than those in other organs analyzed. Second, we demonstrated the metabolic GGA labeling from the 13C-labeled mevalonolactone in the human hepatoma-derived cell line, HuH-7. Isotopomer spectral analysis revealed that approximately 80% of the cellular GGA was newly synthesized from mevalonate (MVA) in 12 h and the acid picked up preexisting farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), suggesting that GGA is derived from FPP and GGPP through the MVA pathway. Third, zaragozic acid A, a squalene synthase inhibitor, induced dose-dependent upregulation of endogenous GGA content in HuH-7 cells and their concomitant cell death. These results strongly suggest that a cancer-preventive GGA is biosynthesized via the MVA pathway in mammals.
巻・号 60(3)
ページ 579-593
公開日 2019-3-1
DOI 10.1194/jlr.M090548
PII S0022-2275(20)32620-1
PMID 30622150
PMC PMC6399490
MeSH Animals Bridged Bicyclo Compounds, Heterocyclic / pharmacology Cell Death / drug effects Cell Line, Tumor Diterpenes / metabolism* Male Mevalonic Acid / metabolism* Rats Rats, Wistar Tricarboxylic Acids / pharmacology
IF 4.743
引用数 4
リソース情報
ヒト・動物細胞 HuH-7