2. Academic Validation
  3. Ascofuranone suppresses invasion and F-actin cytoskeleton organization in cancer cells by inhibiting the mTOR complex 1 signaling pathway

Ascofuranone suppresses invasion and F-actin cytoskeleton organization in cancer cells by inhibiting the mTOR complex 1 signaling pathway

  • Cell Oncol (Dordr). 2020 Oct;43(5):793-805. doi: 10.1007/s13402-020-00520-w.
Yun-Jeong Jeong 1,  Soon-Kyung Hwang 1,  Junji Magae 2,  Young-Chae Chang 3 4
Affiliations

Affiliations

  • 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 Research Institute of Biomedical Engineering, Department of Medicine, Catholic University of Daegu School of Medicine, 42472, Deagu, Korea. [email protected].
  • 4 Department of Cell Biology, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, 42472, Daegu, Korea. [email protected].
PMID: 32488849 DOI: 10.1007/s13402-020-00520-w
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

Actin cytoskeleton organization; Ascofuranone; FAK; Tumor metastasis; mTORC1.

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