Tanshinone IIA affects the malignant growth of Cholangiocarcinoma cells by inhibiting the PI3K-Akt-mTOR pathway

Huayuan Liu,Pengcheng Zhu,Ping Zhang,Dongxu Sun,Mengya Wang,Xueying Tan,Guangjun Shi,Caiyun Liu

doi:10.1038/s41598-021-98948-z

Tanshinone IIA affects the malignant growth of Cholangiocarcinoma cells by inhibiting the PI3K-Akt-mTOR pathway

Huayuan Liu, Pengcheng Zhu + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-98948-z

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Abstract

In the present study, we aimed to find the target of Tanshinone IIA (Tan-IIA) in Cholangiocarcinoma by network pharmacology-based prediction and investigate the possible mechanism through experimental verification. In this study, we combined Tan-IIA-specific and Cholangiocarcinoma-specific targets with protein–protein interactions (PPI) to construct a Tan-IIA targets-Cholangiocarcinoma network, and network pharmacology approach was applied to identify potential targets and mechanisms of Tan-IIA in the treatment of Cholangiocarcinoma. The anti-cancer effects of Tan-IIA were investigated by using subcutaneous tumorigenic model in nude mice and in the human Cholangiocarcinoma cell lines in vitro. Our results showed that Tan-IIA treatment considerably suppressed the proliferation and migration of Cholangiocarcinoma cells while inducing apoptosis of Cholangiocarcinoma cells. Western blot results demonstrated that the expression of PI3K, p-Akt, p-mTOR, and mTOR were inhibited by Tan-IIA. Meanwhile, After treatment with Tan-IIA, the level of Bcl2 was downregulated and cleaved caspase-3 expression increased. Further studies revealed that the anticancer effects of Tan-IIA were severely mitigated by pretreatment with a PI3K agonist. Our research provides a new anticancer strategy and strengthens support for the use of Tan-IIA as an anticancer drug for the treatment of CCA.

Highlights

Cholangiocarcinoma (CCA) is an aggressive malignant tumor of the biliary tract that is often challenging to diagnose and treat[1]
The present study suggested that Tanshinone IIA (Tan-IIA) inhibited the proliferation, invasion, and migration of Cholangiocarcinoma cells by inhibiting the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway
The effect of TanIIA on the proliferation of Cholangiocarcinoma cells was detected by CCK8 (Fig. 1A,B). This indicated that compared with the control group, Tan-IIA inhibited the proliferation of Cholangiocarcinoma cells in a time- and dose-dependent manner (Fig. 1A,B)

Summary

Introduction

Cholangiocarcinoma (CCA) is an aggressive malignant tumor of the biliary tract that is often challenging to diagnose and treat[1] It is the second most common primary malignancy, and its incidence has increased significantly in recent decades[2,3]. A network pharmacological analysis identified common targets for Tan-IIA and Cholangiocarcinoma disease, and KEGG and GO analyses revealed that these common targets were enriched in pathways associated with PI3K-Akt. It is well known that in human cancers, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is the most common aberrant kinase cascade signaling pathway that promotes tumor cell proliferation through the activation of growth factor receptors such as insulin-like growth. The present study suggested that Tan-IIA inhibited the proliferation, invasion, and migration of Cholangiocarcinoma cells by inhibiting the PI3K/Akt/mTOR pathway. Tan-IIA upregulated the level of cleaved caspase-3 and suppressed the expression of Bcl[2], which induced apoptosis of Cholangiocarcinoma cells

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