Ascofuranone suppresses invasion and F-actin cytoskeleton organization in cancer cells by inhibiting the mTOR complex 1 signaling pathway.
Cell Oncol (Dordr)
; 43(5): 793-805, 2020 Oct.
Article
en En
| MEDLINE
| ID: mdl-32488849
ABSTRACT
PURPOSE:
Ascofuranone is an antiviral antibiotic that is known to exert multiple anti-tumor effects, including cell cycle arrest, inhibition of mitochondrial respiration, and inhibition of angiogenesis. In this study, we investigated the molecular mechanisms underlying the anti-metastatic effects of ascofuranone in insulin-like growth factor-I (IGF-1)-responsive cancer cells.METHODS:
The inhibitory effect of ascofuranone on cancer cell migration and invasion was assessed using scratch wound healing and Matrigel invasion assays, respectively. F-actin cytoskeleton organization was assessed using FITC conjugated phalloidin staining. Target gene expression was evaluated using Western blotting and gene silencing was performed using siRNA transfections. Finally, the anti-metastatic effect of ascofuranone was investigated in vivo.RESULTS:
We found that ascofuranone suppressed IGF-1-induced cell migration, invasion and motility in multiple cancer cell lines. The effects of ascofuranone on actin cytoskeleton organization were found to be mediated by suppression of the mTOR/p70S6K/4EBP1 pathway. Ascofuranone inhibited IGF-1-induced mTOR phosphorylation and actin cytoskeleton organization via upregulation of AMPK and downregulation of Akt phosphorylation. It also selectively suppressed the IGF-1-induced mTOR complex (mTORC)1 by phosphorylation of Raptor, but did not affect mTORC2. Furthermore, we found that focal adhesion kinase (FAK) activation decreased in response to ascofuranone, rapamycin, compound C and wortmannin treatment. Finally, we found that ascofuranone suppressed phosphorylation of FAK and mTOR and dephosphorylation of Raptor in cancerous metastatic lung tissues in vivo.CONCLUSIONS:
Our data indicate that ascofuranone suppresses IGF-1-induced cancer cell migration and invasion by blocking actin cytoskeleton organization and FAK activation through inhibition of the mTORC1 pathway, and reveal a novel anti-metastatic function of this compound.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sesquiterpenos
/
Citoesqueleto de Actina
/
Transducción de Señal
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Actinas
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Diana Mecanicista del Complejo 1 de la Rapamicina
/
Neoplasias
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Oncol (Dordr)
Año:
2020
Tipo del documento:
Article