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

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Abstract

Background

Targeting 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.

Methods

Here, 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.

Results

We 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.

Conclusions

Briefly, 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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12935-021-02223-0.

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Most cited references 54

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UniProt: a worldwide hub of protein knowledge

(2018)

Abstract The UniProt Knowledgebase is a collection of sequences and annotations for over 120 million proteins across all branches of life. Detailed annotations extracted from the literature by expert curators have been collected for over half a million of these proteins. These annotations are supplemented by annotations provided by rule based automated systems, and those imported from other resources. In this article we describe significant updates that we have made over the last 2 years to the resource. We have greatly expanded the number of Reference Proteomes that we provide and in particular we have focussed on improving the number of viral Reference Proteomes. The UniProt website has been augmented with new data visualizations for the subcellular localization of proteins as well as their structure and interactions. UniProt resources are available under a CC-BY (4.0) license via the web at https://www.uniprot.org/.

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The Immune Landscape of Cancer

Fadlo Khuri, Natália Aredes, Jung Lee … (2018)

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

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Ultrastructural Characterization of the Lower Motor System in a Mouse Model of Krabbe Disease

Valentina Cappello, Laura Marchetti, Paola Parlanti … (2016)

Krabbe disease (KD) is a neurodegenerative disorder caused by the lack of β- galactosylceramidase enzymatic activity and by widespread accumulation of the cytotoxic galactosyl-sphingosine in neuronal, myelinating and endothelial cells. Despite the wide use of Twitcher mice as experimental model for KD, the ultrastructure of this model is partial and mainly addressing peripheral nerves. More details are requested to elucidate the basis of the motor defects, which are the first to appear during KD onset. Here we use transmission electron microscopy (TEM) to focus on the alterations produced by KD in the lower motor system at postnatal day 15 (P15), a nearly asymptomatic stage, and in the juvenile P30 mouse. We find mild effects on motorneuron soma, severe ones on sciatic nerves and very severe effects on nerve terminals and neuromuscular junctions at P30, with peripheral damage being already detectable at P15. Finally, we find that the gastrocnemius muscle undergoes atrophy and structural changes that are independent of denervation at P15. Our data further characterize the ultrastructural analysis of the KD mouse model, and support recent theories of a dying-back mechanism for neuronal degeneration, which is independent of demyelination.

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Author and article information

Contributors

Wei Xiao: xw_kanion@163.com

Chao Huang:

ORCID: http://orcid.org/0000-0003-1186-0973

huangchao1989@nwafu.edu.cn

Yonghua Wang: yh_wang@nwafu.edu.cn

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2867

Publication date (Electronic): 12 October 2021

Publication date PMC-release: 12 October 2021

Publication date Collection: 2021

Volume: 21

Electronic Location Identifier: 529

Affiliations

[1 ]GRID grid.412262.1, ISNI 0000 0004 1761 5538, Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, , Northwest University, ; Xi’an, China

[2 ]GRID grid.452789.5, State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, , Jiangsu Kanion Parmaceutical, Co., Ltd, ; Lianyungang, China

[3 ]GRID grid.144022.1, ISNI 0000 0004 1760 4150, Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Science, , Northwest A&F University, ; Yangling, 712100 China

Author information

Chao Huang http://orcid.org/0000-0003-1186-0973

Article

Publisher ID: 2223

DOI: 10.1186/s12935-021-02223-0

PMC ID: 8507331

PubMed ID: 34641869

SO-VID: f171834b-76d8-45de-b65d-817c1e09517b

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 3 May 2021

Date accepted : 23 September 2021

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tumor microenvironment,nsclc,licorice,systems pharmacology strategy

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tumor microenvironment, nsclc, licorice, systems pharmacology strategy