論文 - 詳細
| RRC ID | 54762 |
|---|---|
| 著者 | Yamada S, Yamazaki D, Kanda Y. |
| タイトル | 5-Fluorouracil inhibits neural differentiation via Mfn1/2 reduction in human induced pluripotent stem cells. |
| ジャーナル | J Toxicol Sci |
| Abstract |
5-fluorouracil (5-FU) has been widely used for the treatment of tumors. Regardless of its widespread use as an anti-cancer drug, 5-FU therapy can cause several side effects, including developmental toxicity and neurotoxicity. However, the potential action of 5-FU at the early fetal stage has not yet been completely elucidated. In the present study, we investigated the effect of 5-FU exposure on neural induction, using human induced pluripotent stem cells (iPSCs) as a model of human fetal stage. 5-FU exposure reduced the expression of several neural differentiation marker genes, such as OTX2, in iPSCs. Since the neural differentiation process requires ATP as a source of energy, we next examined intracellular ATP content using iPSCs. We found that 5-FU decreased intracellular ATP levels in iPSCs. We further focused on the effects of 5-FU on mitochondrial dynamics, which plays a role of ATP production. We found that 5-FU induced mitochondrial fragmentation and reduced the level of mitochondrial fusion proteins, mitofusin 1 and 2 (Mfn1/2). Double knockdown of Mfn1/2 genes in iPSCs downregulated the gene expression of OTX2, suggesting that Mfn mediates neural differentiation in iPSCs. Taken together, these results indicate that 5-FU has a neurotoxicity via Mfn-mediated mitochondria dynamics in iPSCs. Thus, mitochondrial dysfunction in iPSCs could be used as a possible marker for cytotoxic effects of drugs. |
| 巻・号 | 43(12) |
| ページ | 727-734 |
| 公開日 | 2018-1-1 |
| DOI | 10.2131/jts.43.727 |
| PMID | 30518710 |
| MeSH | Adenosine Triphosphate / metabolism Antimetabolites, Antineoplastic / toxicity* Fluorouracil / toxicity* GTP Phosphohydrolases / genetics GTP Phosphohydrolases / metabolism* Gene Expression / drug effects Humans Induced Pluripotent Stem Cells / drug effects* Induced Pluripotent Stem Cells / physiology Mitochondria / drug effects* Mitochondria / physiology Mitochondrial Membrane Transport Proteins / genetics Mitochondrial Membrane Transport Proteins / metabolism* Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism* Neurogenesis / drug effects* |
| IF | 1.732 |
| 引用数 | 2 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 253G1(HPS0002) |