IMR Press / FBL / Volume 27 / Issue 5 / DOI: 10.31083/j.fbl2705160
Open Access Original Research
Danshensu Attenuated Epithelial-Mesenchymal Transformation and Chemoresistance of Colon Cancer Cells Induced by Platelets
Yuzhu Cao1,†Keqin Lu1,†Yawen Xia1,†Yufei Wang1Aiyun Wang1,2,3,*Yang Zhao1,4,*
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1 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, 210023 Nanjing, Jiangsu, China
2 Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, 210023 Nanjing, Jiangsu, China
3 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, 210023 Nanjing, Jiangsu, China
4 School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 210023 Nanjing, Jiangsu, China
*Correspondence: wangaiyun@njucm.edu.cn (Aiyun Wang); y.zhao@njucm.edu.cn (Yang Zhao)
These authors contributed equally.
Academic Editor: Josef Jampilek
Front. Biosci. (Landmark Ed) 2022, 27(5), 160; https://doi.org/10.31083/j.fbl2705160
Submitted: 22 March 2022 | Revised: 26 April 2022 | Accepted: 27 April 2022 | Published: 17 May 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Background: The interactions between platelets and tumor cells are well-known to play important roles in the progression of malignant tumors. Danshensu, a main water-soluble component of Salvia miltiorrhiza, can resist platelet aggregation and exert significant anti-tumor effects on various types of tumors. However, whether Danshensu could inhibit the progression of malignant tumors by suppressing the activities of platelets had not been reported. Methods: The effects of Danshensu on the platelet activity and epithelial-mesenchymal transformation (EMT)-like invasive phenotype of SW620 colon cancer cells were assessed by stimulating with the supernatants from co-cultured platelets and SW620 cells with direct contact (SCP). The expression and secretion of proteins were determined by western blot and enzyme-linked immunosorbent assay (ELISA), respectively. Hematoxylin and eosin (H&E) staining was performed to analyzed the histopathology of tumor tissues and immunohistochemical staining was conducted to examine the protein expression in tumors. Results: Co-incubation of SW620 cells with platelets directly or SCP both generated long spindle-shaped invasive phenotype. Pretreatment of platelets with Danshensu (25 μM) inhibited the morphological changes of SW620 cells induced by SCP, which was associated with the inhibitory effects of Danshensu on platelet secretion. Danshensu diminished the secretion of a list of biological factors in SCP, including interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL-1β and vascular endothelial growth factor (VEGF) that are all involved in tumor cell EMT and chemoresistance. Moreover, Danshensu up-regulated the expression of E-cadherin but down-regulated the levels of N-cadherin and Vimentin, resulting in the repression of SW620 cell migration. It was also shown that Danshensu enhanced the sensitivity of SW620 cells to oxaliplatin by suppressing the expression of MDR1. Furthermore, Danshensu could not only reduced the growth of subcutaneous tumors and liver metastasis that induced by SCP, but also down-regulated the expression of MDR1 in vivo. Mechanistic studies revealed that Danshensu suppressed the activation of the TGF-β/Smad signaling pathway. Conclusions: Danshensu attenuated EMT-like characteristics and chemoresistance by inhibiting secretion capability of platelets and activation of the TGF-β/Smad signaling pathway, suggesting that it may be optimized to be a therapeutic agent for fighting against colon cancer.

Keywords
platelet
colon cancer
Danshensu
epithelial mesenchymal transformation
chemoresistance
Figures
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