J Cancer 2019; 10(25):6439-6456. doi:10.7150/jca.32873

Research Paper

Jiedu Sangen Decoction Reverses Epithelial-to-mesenchymal Transition and Inhibits Invasion and Metastasis of Colon Cancer via AKT/GSK-3β Signaling Pathway

Li Yuan1*, Kai Zhang2*, Meng-Meng Zhou3, Harpreet S. Wasan4, Fang-Fang Tao5, Qing-Ying Yan1, Guan Feng1, Yin-Shan Tang6, Min-He Shen2, Sheng-Lin Ma7, Shan-Ming Ruan2,7 ✉

1. The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, china
2. Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, Zhejiang, China
3. Department of traditional Chinese medicine, The First people's Hospital of Quzhou, 324000, Zhejiang, China
4. Department of Cancer Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, W12 0HS, UK
5. Department of Immunology and Microbiology, Basic Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
6. Department of Rehabilitation in Traditional Chinese Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
7. Department of Oncology, The Forth Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, Zhejiang, China
*These authors contributed equally to this work.

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Citation:
Yuan L, Zhang K, Zhou MM, Wasan HS, Tao FF, Yan QY, Feng G, Tang YS, Shen MH, Ma SL, Ruan SM. Jiedu Sangen Decoction Reverses Epithelial-to-mesenchymal Transition and Inhibits Invasion and Metastasis of Colon Cancer via AKT/GSK-3β Signaling Pathway. J Cancer 2019; 10(25):6439-6456. doi:10.7150/jca.32873. Available from http://www.jcancer.org/v10p6439.htm

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Abstract

Ethnopharmacology relevance: Jiedu Sangen Decoction (JSD), an empirical prescription of Traditional Chinese Medicine (TCM), has been reported to inhibit invasion and metastasis of colon cancer in our previous study. The aim of this study was to investigate the mechanism of JSD-triggered inhibition of invasion and metastasis in colon cancer.

Methods: In vitro, AKT1 knockdown (si-AKT1) or overexpression (oe-AKT1) cells were successfully constructed both in SW480 and SW620 cell lines. Si-AKT1 and oe-AKT1 cells were then treated with or without JSD. Cell invasion, metastasis potential and expression of epithelial-mesenchymal transformation (EMT)-related and AKT1/GSK-3β proteins were then observed by wound healing, transwell, and western blot assays. In vivo, liver metastasis model mice were developed by inoculating SW480 cells. After JSD diet intervention, living fluorescence imaging and weight measurements were carried out to investigate JSD induced inhibition effects on liver metastasis of colon cancer. Immunohistochemistry and western blot assays were performed to observe tissue features and detect protein expression.

Results: Invasion and metastasis potential, as well as EMT of colon cancer, can be markedly inhibited by JSD treatment or AKT1 knockdown, while enhanced by AKT1 overexpression. JSD-induced inhibition effects were significantly weakened when AKT1 was knocked down, while clearly enhanced when AKT1 was overexpressed. Additionally, JSD could lead to an increase in expression of E-cadherin, and a decrease in expression of N-cadherin, Vimentin, p-AKT1, AKT1, p- GSK-3β, Snail, Slug, and Twist in colon cancer cells.

Conclusion: JSD reverses EMT and inhibits invasion and metastasis of colon cancer through the AKT/GSK-3β signaling pathway.

Keywords: Colon Cancer, Jiedu Sangen Decoction (JSD), Epithelial-mesenchymal transformation (EMT), invasion, metastasis, AKT/GSK-3β signaling pathway