Wogonin Induces Apoptosis and Reverses Sunitinib Resistance of Renal Cell Carcinoma Cells via Inhibiting CDK4-RB Pathway.

Yong Wang,Wenfu Wang,Shouzhen Chen,Benkang Shi,Shuna Sun,Yangyang Xia,Lipeng Chen,Jianfeng Cui,Yaofeng Zhu,Xuewen Jiang,Guangyi Liu,Yongxin Zou,Lei Zhang

doi:10.3389/fphar.2020.01152

Abstract

Wogonin, an active component derived from Scutellaria baicalensis, has shown anti-tumor activities in several malignancies. However, the roles of wogonin in RCC cells remain elusive. Here, we explored the effects of wogonin on RCC cells and the underlying mechanisms. We found that wogonin showed significant cytotoxic effects against RCC cell lines 786-O and OS-RC-2, with much lower cytotoxic effects on human normal embryonic kidney cell line HEK-293 cells. Wogonin treatment dramatically inhibited the proliferation, migration, and invasion of RCC cells. We further showed that by inhibiting CDK4-RB pathway, wogonin transcriptionally down-regulated CDC6, disturbed DNA replication, induced DNA damage and apoptosis in RCC cells. Moreover, we found that the levels of p-RB, CDK4, and Cyclin D1 were up-regulated in sunitinib resistant 786-O, OS-RC-2, and TK-10 cells, and inhibition of CDK4 by palbociclib or wogonin effectively reversed the sunitinib resistance, indicating that the hyperactivation of CDK4-RB pathway may at least partially contribute to the resistance of RCC to sunitinib. Together, our findings demonstrate that wogonin could induce apoptosis and reverse sunitinib resistance of RCC cells via inhibiting CDK4-RB pathway, thus suggesting a potential therapeutic implication in the future management of RCC patients.

Highlights

Renal cell carcinomas (RCCs), arising from the renal epithelium, account for approximately 85% of kidney cancers
MTT assays showed that wogonin significantly reduced the growth of human RCC overall survival (OS)-RC-2 and 786-O cells (Figure 1A), and the proliferative inhibitory effects of wogonin were in a concentration-dependent manner (Figure 1B)
MTT assays showed that inhibitive rate of wogonin at 80 mM on human normal embryonic kidney cell line HEK-293 cells was only about 20% compared with an inhibitive rate of more than 70% on RCC cells (Supplementary Figure 1C)

Summary

Introduction

Renal cell carcinomas (RCCs), arising from the renal epithelium, account for approximately 85% of kidney cancers. A natural flavonoid derived from Scutellaria baicalensis Georgi, has been reported to possess anti-tumour activities against various types of cancer (Baumann et al, 2008; Zhao et al, 2010; Yao et al, 2014) via different ways, such as increasing intracellular reactive oxygen species (ROS) (Qian et al, 2014), inducing apoptosis (Hu et al, 2015), arresting cell cycle (Lu et al, 2015) and reversing drug resistance (Kim et al, 2016). Whether wogonin possesses anti-tumour activities in RCC remains unknown

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Results

Conclusion