論文 - 詳細
| RRC ID | 54837 |
|---|---|
| 著者 | Ogiwara H, Takahashi K, Sasaki M, Kuroda T, Yoshida H, Watanabe R, Maruyama A, Makinoshima H, Chiwaki F, Sasaki H, Kato T, Okamoto A, Kohno T. |
| タイトル | Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers. |
| ジャーナル | Cancer Cell |
| Abstract |
ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species. The vulnerability of ARID1A-deficient cancer cells results from low basal levels of GSH due to impaired expression of SLC7A11. The SLC7A11-encoded cystine transporter supplies cells with cysteine, a key source of GSH, and its expression is enhanced by ARID1A-mediated chromatin remodeling. Thus, ARID1A-deficient cancers are susceptible to synthetic lethal targeting of GCLC. |
| 巻・号 | 35(2) |
| ページ | 177-190.e8 |
| 公開日 | 2019-2-11 |
| DOI | 10.1016/j.ccell.2018.12.009 |
| PII | S1535-6108(18)30581-6 |
| PMID | 30686770 |
| MeSH | Amino Acid Transport System y+ / genetics Amino Acid Transport System y+ / metabolism Animals Antineoplastic Agents / pharmacology* Apoptosis / drug effects* DNA-Binding Proteins Enzyme Inhibitors / pharmacology* Female Glutamate-Cysteine Ligase / antagonists & inhibitors* Glutamate-Cysteine Ligase / metabolism Glutathione / metabolism* HCT116 Cells Humans Mice, Inbred BALB C Mice, Nude Molecular Targeted Therapy Nuclear Proteins / deficiency* Nuclear Proteins / genetics Ovarian Neoplasms / drug therapy* Ovarian Neoplasms / genetics Ovarian Neoplasms / metabolism Ovarian Neoplasms / pathology Oxidative Stress / drug effects* Quinuclidines / pharmacology* Transcription Factors / deficiency* Transcription Factors / genetics Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| IF | 23.916 |
| 引用数 | 24 |
| リソース情報 | |
| ヒト・動物細胞 | JHUEM-2(RCB1551) |