Licorice extract inhibits growth of non-small cell lung cancer by down-regulating CDK4-Cyclin D1 complex and increasing CD8+ T cell infiltration

Ruijie Yang,Chunli Zheng,Ruifei Huang,Chao Huang,Jinglin Zhu,Wei Xiao,Jiangna Yan,Yonghua Wang,Yue Xiao

doi:10.1186/s12935-021-02223-0

Abstract

BackgroundTargeting tumor microenvironment (TME) may provide therapeutic activity and selectivity in treating cancers. Therefore, an improved understanding of the mechanism by which drug targeting TME would enable more informed and effective treatment measures. Glycyrrhiza uralensis Fisch (GUF, licorice), a widely used herb medicine, has shown promising immunomodulatory activity and anti-tumor activity. However, the molecular mechanism of this biological activity has not been fully elaborated.MethodsHere, potential active compounds and specific targets of licorice that trigger the antitumor immunity were predicted with a systems pharmacology strategy. Flow cytometry technique was used to detect cell cycle profile and CD8+ T cell infiltration of licorice treatment. And anti-tumor activity of licorice was evaluated in the C57BL/6 mice.ResultsWe reported the G0/G1 growth phase cycle arrest of tumor cells induced by licorice is related to the down-regulation of CDK4-Cyclin D1 complex, which subsequently led to an increased protein abundance of PD-L1. Further, in vivo studies demonstrated that mitigating the outgrowth of NSCLC tumor induced by licorice was reliant on increased antigen presentation and improved CD8+ T cell infiltration.ConclusionsBriefly, our findings improved the understanding of the anti-tumor effects of licorice with the systems pharmacology strategy, thereby promoting the development of natural products in prevention or treatment of cancers.

Highlights

Lung cancer is the most prevalent diagnosed cancer worldwide and a major contributor of cancer mortality
Predicted by the weighted ensemble similarity method (WES) [20] and systematic drug targeting tool (SysDT) [21], we found that these 23 ingredients in licorice were investigated interacted with 109 targets
As our results showed that licorice down-regulates CDK4-Cyclin D1expression to arrest cell cycle progression, we probed whether licorice participated in variation of PD-L1

Summary

Introduction

Lung cancer is the most prevalent diagnosed cancer worldwide and a major contributor of cancer mortality. Immunotherapy targeting T cells has increasingly shown its potentiality in the treatment of a wide variety of solid tumors, such as NSCLC [4,5,6]. It is the fact that still only a small fraction of patients obtain long-term benefit, Zhu et al Cancer Cell Int (2021) 21:529 which is likely correlated with the complex network of the tumor microenvironment (TME) [7]. TME, a complex physical and biochemical system, plays a pivotal role in tumor initiation, progression, metastasis, and drug resistance [8]. It contains cells of the immune system, tumor cells, tumor vasculature and extracellular matrices (ECM) [9]. The molecular mechanism of this biological activity has not been fully elaborated

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Conclusion