論文 - 詳細
| RRC ID | 53382 |
|---|---|
| 著者 | Wu L, Zhou B, Oshiro-Rapley N, Li M, Paulo JA, Webster CM, Mou F, Kacergis MC, Talkowski ME, Carr CE, Gygi SP, Zheng B, Soukas AA. |
| タイトル | An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer. |
| ジャーナル | Cell |
| Abstract |
Metformin has utility in cancer prevention and treatment, though the mechanisms for these effects remain elusive. Through genetic screening in C. elegans, we uncover two metformin response elements: the nuclear pore complex (NPC) and acyl-CoA dehydrogenase family member-10 (ACAD10). We demonstrate that biguanides inhibit growth by inhibiting mitochondrial respiratory capacity, which restrains transit of the RagA-RagC GTPase heterodimer through the NPC. Nuclear exclusion renders RagC incapable of gaining the GDP-bound state necessary to stimulate mTORC1. Biguanide-induced inactivation of mTORC1 subsequently inhibits growth through transcriptional induction of ACAD10. This ancient metformin response pathway is conserved from worms to humans. Both restricted nuclear pore transit and upregulation of ACAD10 are required for biguanides to reduce viability in melanoma and pancreatic cancer cells, and to extend C. elegans lifespan. This pathway provides a unified mechanism by which metformin kills cancer cells and extends lifespan, and illuminates potential cancer targets. PAPERCLIP. |
| 巻・号 | 167(7) |
| ページ | 1705-1718.e13 |
| 公開日 | 2016-12-15 |
| DOI | 10.1016/j.cell.2016.11.055 |
| PII | S0092-8674(16)31667-1 |
| PMID | 27984722 |
| PMC | PMC5390486 |
| MeSH | Acyl-CoA Dehydrogenase / genetics Aging Animals Body Size Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cell Line, Tumor DNA-Binding Proteins / metabolism Humans Longevity Mechanistic Target of Rapamycin Complex 1 Metformin / pharmacology* Mitochondria / metabolism Monomeric GTP-Binding Proteins / metabolism Multiprotein Complexes / metabolism Neoplasms / drug therapy Nuclear Pore / metabolism Oxidative Phosphorylation Signal Transduction / drug effects TOR Serine-Threonine Kinases / metabolism Transcription Factors / metabolism |
| IF | 38.637 |
| 引用数 | 82 |
| 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 | 167 |
| 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 | |
| 線虫 | tm1944 |