Ascofuranone suppresses invasion and F-actin cytoskeleton organization in cancer cells by inhibiting the mTOR complex 1
- PDF / 2,894,795 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 64 Downloads / 180 Views
ORIGINAL PAPER
Ascofuranone suppresses invasion and F-actin cytoskeleton organization in cancer cells by inhibiting the mTOR complex 1 signaling pathway Yun-Jeong Jeong 1 & Soon-Kyung Hwang 1 & Junji Magae 2 & Young-Chae Chang 1,3 Received: 24 July 2019 / Revised: 29 March 2020 / Accepted: 15 April 2020 # International Society for Cellular Oncology 2020
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. Keywords Tumor metastasis . Ascofuranone . mTORC1 . FAK . Actin cytoskeleton organization
1 Introduction Tumor metastasis is a complex process in which cells migrate from the primary tumor site to other tissues and form
* Young-Chae Chang [email protected] 1
Research Institute of Biomedical Engineering, Department of Medicine, Catholic University of Daegu School of Medicine, 42472 Deagu, Korea
2
Magae Bioscience Institute, 49-4 Fujimidai, 300-1263 Tsukuba, Japan
3
Department of Cell Biology, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, 42472 Daegu, Korea
secondary tumors, which are the primary cause of patient mortality. Metastasis requires cancer cells to be motile, a prop
Data Loading...
