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

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

doi:10.3389/fphar.2020.586616

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

Front Pharmacol. 2020 Oct 29:11:586616. doi: 10.3389/fphar.2020.586616. eCollection 2020.

Authors

Qing Song^{1

2

3}, Liu Yang^{1

2

4}, Zhifen Han^{1

2}, Xinnan Wu^{1

2}, Ruixiao Li^{1

2}, Lihong Zhou^{1

2}, Ningning Liu^{1

2}, Hua Sui^{1

2}, Jianfeng Cai⁵, Yan Wang^{1

2}, Qing Ji^{1

2}, Qi Li^{1

2}

Affiliations

¹ Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
³ Department of Medical Oncology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China.
⁴ Department of Oncology, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁵ Department of Chemistry, University of South Florida, Tampa, FL, United States.

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.

Keywords: colorectal cancer; epithelial-to-mesenchymal transition; tanshinone IIA; β-arrestin1; β-catenin signaling pathway.