| 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
|
| リソース情報 |
| ヒト・動物細胞 |
HCT116(RCB2979)
DU145(RCB2143)
LNCap.FGC(RCB2144)
B16F10(RCB2630) |
