| RRC ID |
63636
|
| 著者 |
Rathore R, Caldwell KE, Schutt C, Brashears CB, Prudner BC, Ehrhardt WR, Leung CH, Lin H, Daw NC, Beird HC, Giles A, Wang WL, Lazar AJ, Chrisinger JSA, Livingston JA, Van Tine BA.
|
| タイトル |
Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma.
|
| ジャーナル |
Cell Rep
|
| Abstract |
Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma.
|
| 巻・号 |
34(4)
|
| ページ |
108678
|
| 公開日 |
2021-1-26
|
| DOI |
10.1016/j.celrep.2020.108678
|
| PII |
S2211-1247(20)31667-3
|
| PMID |
33503424
|
| PMC |
PMC8552368
|
| MeSH |
Bone Neoplasms / metabolism*
Bone Neoplasms / pathology
Cell Line, Tumor
Humans
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Osteosarcoma / metabolism*
Osteosarcoma / pathology
Phosphoglycerate Dehydrogenase / metabolism*
Signal Transduction
|
| IF |
8.109
|
| リソース情報 |
| ヒト・動物細胞 |
NOS-1(RCB1032) |
