J Cancer 2019; 10(9):1997-2005. doi:10.7150/jca.29933

Research Paper

Cytochalasin H Inhibits Angiogenesis via the Suppression of HIF-1α Protein Accumulation and VEGF Expression through PI3K/AKT/P70S6K and ERK1/2 Signaling Pathways in Non-Small Cell Lung Cancer Cells

Yuefan Ma1,2*, Zihan Xiu1,2*, Zhiyuan Zhou1,2, Bingyu Huang1,2, Jiao Liu1,2, Xiaofeng Wu1,2, Sanzhong Li1,2, Xudong Tang 1,2,3,4✉

1. Collaborative innovation center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang 524023, P.R. China
2. Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
3. Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, P.R. China
4. Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, P.R. China.
* These authors contribute equally to this work.

Abstract

Our previous study has demonstrated that cytochalasin H (CyH) isolated from mangrove-derived endophytic fungus induces apoptosis and inhibits migration in A549 non-small cell lung cancer (NSCLC) cells. In this study, we further explored the effect of CyH on angiogenesis in NSCLC cells and the underlying molecular mechanisms. A549 and H460 NSCLC cells were treated with different concentrations of CyH for 24 h. The effects of CyH on NSCLC angiogenesis in vitro and in vivo were investigated. Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in xenografted NSCLC of nude mice was analyzed by immunohistochemistry. ELISA was used to analyze the concentration of VEGF in the conditioned media derived from treated and untreated NSCLC cells. Western blot was performed to detect the levels of HIF-1α, p-AKT, p-P70S6K, and p-ERK1/2 proteins, and RT-qPCR was used to determine the levels of HIF-1α and VEGF mRNA in A549 and H460 cells. Our results showed that CyH significantly inhibited angiogenesis in vitro and in vivo, and suppressed the hemoglobin content and HIF-1α and VEGF protein expression in xenografted NSCLC tissues of nude mice. Meanwhile, CyH inhibited the secretion of VEGF protein and the expression of HIF-1α protein in A549 and H460 cells. Moreover, CyH had a significant inhibitory effect on VEGF mRNA expression but had no effect on HIF-1α mRNA expression, and CyH inhibited HIF-1α protein expression by promoting the degradation of HIF-1α protein in A549 and H460 cells. Additionally, CyH dramatically inhibited AKT, P70S6K, and ERK1/2 activation in A549 and H460 cells. Taken together, our results suggest that CyH can inhibit NSCLC angiogenesis by the suppression of HIF-1α protein accumulation and VEGF expression through PI3K/AKT/P70S6K and ERK1/2 signaling pathways.

Keywords: cytochalasin H (CyH), angiogenesis, hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), PI3K/AKT/P70S6K, ERK1/2, non-small cell lung cancer (NSCLC), mangrove

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How to cite this article:
Ma Y, Xiu Z, Zhou Z, Huang B, Liu J, Wu X, Li S, Tang X. Cytochalasin H Inhibits Angiogenesis via the Suppression of HIF-1α Protein Accumulation and VEGF Expression through PI3K/AKT/P70S6K and ERK1/2 Signaling Pathways in Non-Small Cell Lung Cancer Cells. J Cancer 2019; 10(9):1997-2005. doi:10.7150/jca.29933. Available from http://www.jcancer.org/v10p1997.htm