| 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
|
| リソース情報 |
| ヒト・動物細胞 |
NOS-1(RCB1032) |
