Tanshinone IIA Inhibits Epithelial-to-Mesenchymal Transition Through Hindering Œ≤-Arrestin1 Mediated Œ≤-Catenin Signaling Pathway in Colorectal Cancer
Authors: Zhifen Han
Qing Ji
Xinnan Wu
Ningning Liu
Lihong Zhou
Yan Wang
Qing Song
Ruixiao Li
Qi Li
Liu Yang
Hua Sui
Jianfeng Cai
Journal: Frontiers in Pharmacology (2020)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: colorectal cancer; epithelial-to-mesenchymal transition; tanshinone IIA; Œ≤-arrestin1; Œ≤-catenin signaling pathway.
Affiliations: Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China., 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 Œ≤-arrestin1could regulate EMT in CRC partly through Œ≤-catenin signaling pathway. In this work, we investigate whether Tan IIA could regulate EMT in CRC through Œ≤-arrestin1-mediated Œ≤-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 Œ≤-arrestin1 expression, resulting in the increase of GSK-3Œ≤ expression, reduction of Œ≤-catenin nuclear localization, thereby decreased the activity of Œ≤-catenin signaling pathway. Our data revealed a new mechanism of Tan IIA on the suppression of EMT and metastasis in CRC via Œ≤-arrestin1-mediated Œ≤-catenin signaling pathway and provided support for using Tan IIA as anti-metastatic agents in CRC. 

Retracted: No

PubPeer comments:
 Two images in Figure 3A appear to overlap, after rotation (red boxes). ***  , 
 An image in Figure 5A seems to appear in Figure 7F of a later paper with overlapping authorship, where it seems to be described differently: Frontiers in Cell and Developmental Biology (2021), doi: 10.3389 fcell.2021.650067, discussed here: https: pubpeer.com publications 33BCDDCFDD6D327CFEBC5899EE4E7A. Could the authors please check? ***  , 
 #1 Dear Actinopolyspora biskrensis, We thank you very much for this important issue. In figure 3A, the picture (Tan IIA 5u03bcM) was misused due to our carelessness in data collection. After checking the original data, we will use the correct picture (Tan IIA 5u03bcM) to replace the wrong one. Moreover, we will ask for the editor office of Frontiers in Pharmacology to correct our mistake. Most importantly, we will strive to eliminate such mistakes in our future work. We thank again for your kind raising of this important issue, which are very helpful for improving the quality of our work. Your valuable comments are very welcome again.  #2 Dear Actinopolyspora biskrensis, We thank you for pointing out the important mistake in Figure 5A. We are very sorry for our mistake. Our experiments in referred two papers were performed at the same time, and therefore some data was deal with together, including the immunohistochemical results of Snail. In figure 5A (Frontiers in Pharmacology, 2020), by checking the original data, we find that we have misused one immunohistochemical picture of Snail (Tan IIA-M). We will provide the correct picture (Tan IIA-M) to replace the wrong one to make up for the mistake. However, in the Figure 7F of the paper in Frontiers in Cell and Developmental Biology (2021), the immunohistochemical pictures for Snail were right provided. To correct our mistake in Figure 5A (Frontiers in Pharmacology, 2020), we will ask for the editor office of Frontiers in Pharmacology to provide the right data. In the future work, we will try our best to avoid such mistakes. We thank again for your raising of this important issue. Your valuable comments are very welcome again.  , 
 #3 Thank you for responding promptly. 1. In your reply to the #1 concern, you indicate that the error occurred during data collection. Does this then affect the quantification illustrated in Figure 3B (shown below)? 2. Could the authors please provide the original scans of the Western blots in Figure 3i and 3k? The contrast of the published images seem too high which removes the background details. Thank you. ***  , 
 #4 Dear Actinopolyspora biskrensis, We thank you very much for this important issue. In figure 3A, we use the correct picture (Tan IIA 5u03bcM) to replace the wrong one and adjust the corresponding quantitative picture in Figure 3B. We will ask for the editor office of Frontiers in Pharmacology to provide the right data. In the future work, we will try our best to avoid such mistakes. We provide the original scans of the Western blots in Figure 3I and 3K for better understanding. We thank again for your kind raising of this important issue, which are very helpful for improving the quality of our work. Your valuable comments are very welcome again.   , 
 #5 I thank the authors again for their prompt reply. Are the uncropped scans of the Western blots still available? While the shading around the updated image you provided is more in line with what is expected to be published, I would appreciate seeing the original gels. , 
 #6 Dear Actinopolyspora biskrensis, We thank you very much for this important issue. According to your requirements, we provide the original scans of the Western blots in Figure 3I and 3K for better understanding. We thank again for your kind raising of this important issue, which are very helpful for improving the quality of our work. Your valuable comments are very welcome again.  , 
 #7 Thank you for providing these images. I would characterize these as cut blots, not the original full blot scan. For your reference, you may wish to review this article: https: www.nature.com articles s41401-020-00539-7, which includes this illustration:  ,