論文 - 詳細
| RRC ID | 68629 |
|---|---|
| 著者 | Heishima K, Sugito N, Soga T, Nishikawa M, Ito Y, Honda R, Kuranaga Y, Sakai H, Ito R, Nakagawa T, Ueda H, Akao Y. |
| タイトル | Petasin potently inhibits mitochondrial complex I-based metabolism that supports tumor growth and metastasis. |
| ジャーナル | J Clin Invest |
| Abstract |
Mitochondrial electron transport chain complex I (ETCC1) is the essential core of cancer metabolism, yet potent ETCC1 inhibitors capable of safely suppressing tumor growth and metastasis in vivo are limited. From a plant extract screening, we identified petasin (PT) as a highly potent ETCC1 inhibitor with a chemical structure distinct from conventional inhibitors. PT had at least 1700 times higher activity than that of metformin or phenformin and induced cytotoxicity against a broad spectrum of tumor types. PT administration also induced prominent growth inhibition in multiple syngeneic and xenograft mouse models in vivo. Despite its higher potency, it showed no apparent toxicity toward nontumor cells and normal organs. Also, treatment with PT attenuated cellular motility and focal adhesion in vitro as well as lung metastasis in vivo. Metabolome and proteome analyses revealed that PT severely depleted the level of aspartate, disrupted tumor-associated metabolism of nucleotide synthesis and glycosylation, and downregulated major oncoproteins associated with proliferation and metastasis. These findings indicate the promising potential of PT as a potent ETCC1 inhibitor to target the metabolic vulnerability of tumor cells. |
| 巻・号 | 131(17) |
| 公開日 | 2021-9-1 |
| DOI | 10.1172/JCI139933 |
| PII | 139933 |
| PMID | 34623325 |
| PMC | PMC8409585 |
| MeSH | Adenosine Triphosphate / metabolism Animals Antineoplastic Agents, Phytogenic / chemistry Antineoplastic Agents, Phytogenic / pharmacology* Cell Line, Tumor Electron Transport Complex I / antagonists & inhibitors* Electron Transport Complex I / metabolism Endoplasmic Reticulum Stress / drug effects Female Humans Lung Neoplasms / drug therapy Lung Neoplasms / metabolism Lung Neoplasms / secondary Metabolome / drug effects Metformin / pharmacology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Nude Neoplasm Metastasis / prevention & control Neoplasms, Experimental / drug therapy* Neoplasms, Experimental / metabolism* Neoplasms, Experimental / pathology Petasites / chemistry Phenformin / pharmacology Sesquiterpenes / chemistry Sesquiterpenes / pharmacology* Unfolded Protein Response / drug effects Xenograft Model Antitumor Assays |
| IF | 11.864 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 45 |
| 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 | HCT116(RCB2979) DU145(RCB2143) LNCap.FGC(RCB2144) B16F10(RCB2630) |