Elsevier

Biomedicine & Pharmacotherapy

Volume 105, September 2018, Pages 758-765
Biomedicine & Pharmacotherapy

Tanshinone IIA inhibits cervix carcinoma stem cells migration and invasion via inhibiting YAP transcriptional activity

https://doi.org/10.1016/j.biopha.2018.06.028Get rights and content

Highlights

  • A new critical role of Tanshinone IIA in CC stem cells progression is proposed.

  • The mechanisms of Tanshinone IIA in CC stem cells progression are further studied.

  • A novel mode of regulation of YAP by HuR in CC cells.

  • The novel mechanism provides new potential drug for CC.

Abstract

This study aims to explore the effects and related mechanisms of Tanshinone IIA in cervix carcinoma (CC) stemness-like cells migration, invasion, stemness and chemotherapeutical sensitivity. Here, we found that Tanshinone IIA suppressed CC stemness-like cells migration and invasion in a concentration- and time-dependent manner. And consistent results were obtained in CC cells stemness characterized as the decrease of CC stemness markers expression and cells spheroid formation ability. Mechanistically, we found that Tanshinone IIA suppressed RNA binding protein HuR translocation from nuclear to cytoplasm, and thus reduced YAP mRNAs stability and transcriptional activity. Importantly, overexpression YAP-5SA rescued the inhibition of Tanshinone IIA on CC cells stemness. Furthermore, Tanshinone IIA enhanced adriamycin sensitivity in CC stemness-like cells, this effect was attenuated by YAP-5SA overexpression too. Therefore, Tanshinone IIA could suppress CC stemness-like cells migration and invasion by inhibiting YAP transcriptional activity.

Introduction

Cervical cancer (CC) is one of the common gynecological malignant tumors that seriously threaten women health, and is closely related with the human papillomavirus (HPV) infection and the HPV vaccine has achieved remarkable results in the prevention of cervical cancer [1]. Although surgery, radiotherapy and chemotherapy have exerted better effects on early CC treatment, the efficacy on local stage and metastatic CC is limited and the survival rate of recurrent CC is lower [2]. Cancer stem cells (CSCs) have been confirmed to be involved in tumor initiation, metastasis and recurrence [3], thus, finding novel drugs that could eliminate CC CSCs or suppress CC cells stemness may provide potential methods or new clues for treating CC patients.

Danshen (Salvia miltiorrhiza Bunge) has been used extensively and historically in China to treat various diseases, including cardiovascular diseases, cerebrovascular diseases and cancer [4]. TanshinoneⅡA is one of the major monomer extracted from root of Salvia miltiorrhiza (RSM), which holds various activities, especially in tumors progression [5] and inflammation [6]. Previous studies have shown that TanshinoneⅡA could inhibit the growth of glioma and breast cancer stem cells [7,8]. However, the roles and related mechanisms of Tanshinone IIA in CC stemness have never been reported.

Hippo pathway is a conservative signaling in mammals, and consists of MST1/2 (mammalian Sterile 20-like kinase 1/2), LATS1/2 (large tumor suppressor 1/2) which could phosphorylate and inactivate the downstream transcriptional effectors YAP/TAZ [9]. YAP/TAZ has been shown to contribute to tumor cells stemness and inhibition of YAP/TAZ transcriptional activity could attenuate CSCs progression [10,11]. Notably, LATS1/2 could suppress breast cancer EMT and metastasis via inactivating YAP/TAZ activity [12]. However, effectors in facilitating the development of YAP/TAZ are frustrated. Therefore, it is an urgent need to find novel YAP/TAZ inhibitors.

RNA binding proteins are a kind of proteins that could bind to and enhance mRNAs stability [13]. HuR, as an RNA binding protein, has been shown to facilitate CSCs progression, such as HuR facilitates cancer stemness of lung cancer cells via regulating miR-873/CDK3 and miR-125a-3p/CDK3 axis [14], and miR-146b-5p overexpression attenuates stemness and radioresistance of glioma stem cells by targeting HuR/lincRNA-p21/beta-catenin pathway [15]. Here, we found that Tanshinone IIA could inhibit HuR translocation from nuclear to cytoplasm. Furthermore, we indicated that HuR directly bound to YAP and enhanced YAP transcriptional activity. Importantly, we showed that Tanshinone IIA attenuated CC cells stemness, CC stem cells migration and invasion in a concentration- and time- dependent manner, these effects were attenuated by YAP-5SA overexpression which could not be phosphorylated by LATS1/2. Finally, we found that Tanshinone IIA enhanced adriamycin sensitivity in CC cells. Therefore, our results suggest that Tanshinone IIA could suppress CC stem cells formation, migration and invasion by activating Hippo pathway.

Section snippets

Cells culture and reagents

CC cells Hela, and C33 A, and healthy primary normal cervical epithelial cells HcerEpic were purchased from the Chinese Academy of Sciences Cell Bank. All of the cell lines were cultured in Dulbecco’s Minimum Essential Medium (DMEM) medium (Gibco,USA) with 10% FBS (fetal bovine serum, Gibco) plus 80 U/ml penicillin and 0.08 mg/ml streptomycin at 37 °C under humidified atmosphere with 5% CO2. Tanshinone IIA (Cat # S2365) and adriamycin (S1208) were purchased from Selleck.cn. pQCXIH-Myc-YAP-5SA

Tanshinone IIA inhibits CC cells stemness in a concentration dependent manner

Firstly, we investigated whether Tanshinone IIA could attenuate CC cells stemness. As expected, Tanshinone IIA decreased the expression of CSCs-related makers (ALDH1 and Nanog) in a concentration dependent manner (Fig. 1AC). Furthermore, the ability of cell spheroid formation was attenuated by Tanshinone IIA in a concentration-dependent manner, characterized as the decrease of the spheres number and size (Fig. 1D and E). Notably, we detected whether Tanshinone IIA held toxicity on healthy

Discussion

CSCs have been proved to be involved in tumor initiation, metastasis, recurrence and chemoresistance [22]. Previous studies have shown that targeting flavin-containing enzymes could eliminate CSCs by inhibiting mitochondrial respiration [23], and CDK4/6 inhibitor could target CSCs in breast cancer [24]. However, there is no drugs reported to target CSCs in CC cells. To the best of our knowledge, this is the first study revealing that Tanshinone IIA could eliminate CC CSCs and enhance adriamycin

Conflicts of interest

The authors declare no conflict of interest.

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      Evodiamine, obtained from the Chinese herb Evodia rutaecarpa Benham, can promote MST1/2-mediated phosphorylation of LATS1/2, resulting in YAP phosphorylation and blocking YAP translocation into the nucleus; evodiamine has been demonstrated to suppress the proliferation of colon CSCs (H. H. Kim et al., 2019; Zhao et al., 2020). In addition, tanshinone IIA and limonin, which are produced from Chinese herbs, have been shown to inhibit the translocation of YAP from the cytoplasm to the nucleus (Qin et al., 2018; W. Y. Zhao et al., 2019) and hence reduce the stemness of cervical CSCs. Recent research highlights the significance of SIRP in the activation of the Hippo signaling system, which promotes cancer growth and metastasis (Xu et al., 2022).

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