論文 - 詳細
| RRC ID | 68730 |
|---|---|
| 著者 | Shikata M, Toyooka T, Komaki Y, Ibuki Y. |
| タイトル | 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced Histone Acetylation via α7nAChR-Mediated PI3K/Akt Activation and Its Impact on γ-H2AX Generation. |
| ジャーナル | Chem Res Toxicol |
| Abstract |
A typical tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is known as a strong carcinogen. We previously reported that metabolized NNK induced histone H2AX phosphorylation (γ-H2AX), a DNA damage-induced histone modification. In this study, we found that NNK globally acetylated histone H3, which affected γ-H2AX generation. Human lung adenocarcinoma A549 was treated with several doses of NNK. NNK induced dose-dependent global histone H3 acetylation (Ac-H3), at 2 to 12 h after the treatment, independent of the cell cycle. The Ac-H3 pattern was not affected by CYP2A13 overexpression unlike γ-H2AX, indicating no requirement of NNK metabolism to induce Ac-H3. Immunofluorescence staining of Ac-H3 was uniform throughout the nucleus, whereas γ-H2AX was formed as foci and did not coincide with Ac-H3. Nicotinic receptor antagonist methyllycaconitine inhibited Ac-H3 and also γ-H2AX. Phosphoinositide-3-kinase (PI3K)/Akt inhibitors, LY294002, wortmannin, and GSK690693, also suppressed both Ac-H3 and γ-H2AX, whereas KU-55933, an inhibitor of ataxia telangiectasia mutated (ATM) upstream of γ-H2AX, inhibited γ-H2AX but not Ac-H3. These results suggested that binding of NNK to the nicotinic acetylcholine receptor (α7nAChR) activated the PI3K/Akt pathway, resulting in Ac-H3. The activated pathway leading to Ac-H3 enhanced γ-H2AX, suggesting that NNK-induced DNA damage is impacted by the α7nAChR-mediated signal transduction pathway. |
| 巻・号 | 34(12) |
| ページ | 2512-2521 |
| 公開日 | 2021-12-20 |
| DOI | 10.1021/acs.chemrestox.1c00287 |
| PMID | 34784199 |
| MeSH | A549 Cells Acetylation / drug effects Chromones / pharmacology Dose-Response Relationship, Drug Histones / antagonists & inhibitors Histones / biosynthesis Histones / metabolism* Humans Morpholines / pharmacology Nitrosamines / pharmacology* Oxadiazoles / pharmacology Phosphatidylinositol 3-Kinases / metabolism* Proto-Oncogene Proteins c-akt / metabolism* Pyrones / pharmacology Tumor Cells, Cultured Wortmannin / pharmacology alpha7 Nicotinic Acetylcholine Receptor / metabolism* |
| IF | 3.184 |
| 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 | MCF7(RCB1904) MRC-5(RCB0218) |