Tanshinone IIA Inhibits Epithelial-to-Mesenchymal Transition Through Hindering β-Arrestin1 Mediated β-Catenin Signaling Pathway in Colorectal Cancer.

Qing Song,Lihong Zhou,Zhifen Han,Liu Yang,Yan Wang,Qi Li,Ningning Liu,Qing Ji,Ruixiao Li,Xinnan Wu,Jianfeng Cai,Hua Sui

doi:10.3389/fphar.2020.586616

Abstract

Tanshinone IIA (Tan IIA) is a major active ingredient extracted from Salvia miltiorrhiza, which has been proved to be able to inhibit metastasis of various cancers including colorectal cancer (CRC). However, the mechanisms of anti-metastatic effect of Tan IIA on CRC are not well explored. A number of studies indicate that epithelial-to-mesenchymal transition (EMT) plays an important role in CRC metastasis, and our previous studies demonstrate that β-arrestin1could regulate EMT in CRC partly through β-catenin signaling pathway. In this work, we investigate whether Tan IIA could regulate EMT in CRC through β-arrestin1-mediated β-catenin signaling pathway both in vivo and in vitro. Our results showed that Tan IIA inhibited lung metastases of CRC cells in vivo and extended the survival time of mice with CRC. In vitro, Tan IIA increased the expression of E-cadherin, decreased the expression of Snail, N-cadherin and Vimentin, thus suppressed EMT and the migratory ability of CRC cells. Further study found that the mechanism of action of Tan IIA in regulating EMT and metastasis is associated with the suppression of β-arrestin1 expression, resulting in the increase of GSK-3β expression, reduction of β-catenin nuclear localization, thereby decreased the activity of β-catenin signaling pathway. Our data revealed a new mechanism of Tan IIA on the suppression of EMT and metastasis in CRC via β-arrestin1-mediated β-catenin signaling pathway and provided support for using Tan IIA as anti-metastatic agents in CRC.

Highlights

Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer-associated death in the world, consisting of over 1.7 million new cases and 861,663 deaths per year (Bray et al, 2018)
Tanshinone IIA (Tan IIA) is a major active ingredient extracted from Salvia miltiorrhiza, which has been proved to be able to inhibit
In vivo imaging results indicated that HCT-116/luc cells migrated to lung tissues after tail injection, and Tan IIA at concentrations of 0.5, 1, and 2 mg/kg (Sui et al, 2017) inhibited the metastatic ability of HCT-116/luc cells in a concentration-dependent manner

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer-associated death in the world, consisting of over 1.7 million new cases and 861,663 deaths per year (Bray et al, 2018). Epithelial-to-mesenchymal transition (EMT) plays a key role in CRC metastasis (Li et al, 2017). During EMT, down-regulation of E-cadherin leads to the loss of cell adhesion, upregulation of Vimentin and N-cadherin causes the reorganization of actin cytoskeleton and promotes cell motility (Guarino et al, 2009). GSK/ β-catenin signaling plays an important role in tumor EMT, invasion and metastasis. Inactivation of GSK-3β phosphorylation facilitates the nuclear localization of β-catenin, leading to the activation of GSK/β-catenin signaling pathway, increasing the expression of snail, ZEB1 and Twist, thereby promoting tumor EMT and metastasis (Wang et al, 2018; Zhang et al, 2018a). Β-arrestin could promote EMT and metastasis through repressing the expression of GSK3β, inhibiting the degradation of β-catenin, thereby activating β-catenin signaling pathway (Supplementary Material for review)

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Conclusion