論文 - 詳細
| RRC ID | 83112 |
|---|---|
| 著者 | Oyama T, Brashears CB, Rathore R, Benect-Hamilton H, Caldwell KE, Dirckx N, Hawkins WG, Van Tine BA. |
| タイトル | PHGDH inhibition and FOXO3 modulation drives PUMA-dependent apoptosis in osteosarcoma. |
| ジャーナル | Cell Death Dis |
| Abstract |
Osteosarcoma is a bone cancer that has been found to be metabolically dependent on the conversion of glucose to serine through the rate-limiting enzyme 3-phosphoglycerate dehydrogenase (PHGDH). The upregulation of PHGDH has been correlated with poor patient survival, and the inhibition of the serine synthesis pathway using targeted small-molecule inhibition of PHGDH induces a rapid metabolic adaptation that prevents cell death due to pro-survival signaling through the mammalian target of rapamycin complex 1 (mTORC1) pathway. Here, PHGDH inhibition in combination with mTORC1 signaling modulation for the treatment of osteosarcoma was evaluated. When combined with PHGDH inhibition, several non-rapalog inhibitors of mTORC1 activated Forkhead box O (FOXO) transcription factor 3 (FOXO3), a transcription factor associated with various cellular processes driving apoptosis. The activation of FOXO3 led to transcriptional activation of the pro-apoptotic gene p53 upregulated modulator of apoptosis (PUMA), inducing apoptosis when combined with PHGDH inhibition. These data suggest a path for the clinical development of PHGDH inhibitors in conjunction with mTORC1 pathway modulators in osteosarcoma. |
| 巻・号 | 16(1) |
| ページ | 89 |
| 公開日 | 2025-2-12 |
| DOI | 10.1038/s41419-025-07378-6 |
| PII | 10.1038/s41419-025-07378-6 |
| PMID | 39934141 |
| PMC | PMC11814296 |
| MeSH | Animals Apoptosis* / drug effects Apoptosis Regulatory Proteins* / genetics Apoptosis Regulatory Proteins* / metabolism Bone Neoplasms / drug therapy Bone Neoplasms / genetics Bone Neoplasms / metabolism Bone Neoplasms / pathology Cell Line, Tumor Forkhead Box Protein O3* / genetics Forkhead Box Protein O3* / metabolism Humans Mechanistic Target of Rapamycin Complex 1* / metabolism Mice Osteosarcoma* / drug therapy Osteosarcoma* / genetics Osteosarcoma* / metabolism Osteosarcoma* / pathology Phosphoglycerate Dehydrogenase* / antagonists & inhibitors Phosphoglycerate Dehydrogenase* / genetics Phosphoglycerate Dehydrogenase* / metabolism Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism Signal Transduction / drug effects |
| IF | 6.304 |
| 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 | 5 |
| 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 | NOS-1(RCB1032) |