Mechanism of Key Ingredient of <italic style="font-style: italic">Astragalus membranaceus</italic> on Lung Adenocarcinoma via PI3K/AKT Signaling Clarified by Utilizing Network Pharmacology Approach and Experimental Validation

WANG Yuan-chun; HUI Jian-rong; XIAO Gang; MA Qiao-lin

doi:10.1007/s11655-022-3681-x

Your Location：

Home >

Browse articles >

Mechanism of Key Ingredient of Astragalus membranaceus on Lung Adenocarcinoma via PI3K/AKT Signaling Clarified by Utilizing Network Pharmacology Approach and Experimental Validation

Original Article | Updated：2023-02-22

- Mechanism of Key Ingredient of Astragalus membranaceus on Lung Adenocarcinoma via PI3K/AKT Signaling Clarified by Utilizing Network Pharmacology Approach and Experimental Validation
- Chinese Journal of Integrative Medicine Vol. 29, Issue 3, Pages: 244-252(2023)
- Affiliations：
  
  1.The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing (210023), China
  2.First Department of Oncology, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province (712000), China
  3.College of Acupuncture-Moxibustion and Tuina, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province (712046), China
  4.First Department of General Surgery, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province (712000), China
- Author bio：
  
  Prof. WANG Yuan-chun, E-mail:yuanchun95@163.com
- Funds：
- DOI：10.1007/s11655-022-3681-x
  CLC：
- Published：2023-03，
  
  Published Online：31 August 2022，
  
  Accepted：09 June 2022
Scan for full text
WANG Yuan-chun, HUI Jian-rong, XIAO Gang, et al. Mechanism of Key Ingredient of Astragalus membranaceus on Lung Adenocarcinoma via PI3K/AKT Signaling Clarified by Utilizing Network Pharmacology Approach and Experimental Validation. [J]. Chinese Journal of Integrative Medicine 29(3):244-252(2023)
DOI：

WANG Yuan-chun, HUI Jian-rong, XIAO Gang, et al. Mechanism of Key Ingredient of Astragalus membranaceus on Lung Adenocarcinoma via PI3K/AKT Signaling Clarified by Utilizing Network Pharmacology Approach and Experimental Validation. [J]. Chinese Journal of Integrative Medicine 29(3):244-252(2023) DOI： 10.1007/s11655-022-3681-x.

摘要

Abstract

Objective:

To investigate the mechanism of the effect of

Astragalus membranaceus

(

A. membranaceus

) on lung adenocarcinoma at the molecular level to elucidate the specific targets according to the network pharmacology approach.

Methods:

The active components of

A. membranaceus

and their potential targets were collected from the Traditional Chinese Medicine Systems Pharmacology Database. Lung adenocarcinoma-associated genes were acquired based on GeneCards

Online Mendelian Inheritance in Man (OMIM)

PharmGKB

and Therapeutic Targets databases. The PI3K/AKT signaling pathway-related genes were obtained using Reactome portal. Networks of "ingredient-target" and "ingredient-target-pathway-disease" were constructed using the Cytoscape3.6.0 software. The relationships among targets were analyzed according protein-protein interaction (PPI) network. Finally

molecular docking was applied to construct the binding conformation between active ingredients and core targets. Cell counting kit 8 (CCK8) and Western blot assays were performed to determine the mechanism of the key ingredient of

A. membranaceus

Results:

A total of 20 active components and their 329 targets

and 7

501 lung adenocarcinoma-related genes and 130 PI3K/AKT signaling pathway-related genes were obtained. According to Venn diagram and PPI network analysis

2 mainly active ingredients

including kaempferol and quercetin

and 6 core targets

including TP53

MAPK1

EGF

AKT1

ERBB2

and EGFR

were identified. The two important active ingredients of

A. membranaceus

kaempferol and quercetin

exert the therapeutic effect in lung adenocarcinoma partly by acting on the 6 core targets (TP53

MAPK1

EGF

AKT1

ERBB2

and EGFR) of PI3K/AKT signaling pathway. Expressions of potential targets in lung adenocarcinoma and normal samples were analyzed by using UALCAN portal and found that ERBB2 was overexpressed in lung adenocarcinoma tissues and upregulation of it correlated with clinicopathological characteristics. Finally

quercetin repressed viabilities of lung adenocarcinoma cells by targeting ERBB2 on PI3K/AKT signaling confirmed by CCK8 and Western blot.

Conclusion:

Our finding unraveled that an active ingredient of

A. membranaceus

quercetin

significantly inhibited the lung adenocarcinoma cells proliferation by repressing ERBB2 level and inactivating the PI3K/AKT signaling pathway.

关键词

Keywords

lung adenocarcinomacompound-target networkmechanism predictionmolecular dockingPI3K/AKT signaling pathwayChinese medicine

references

Kuhn E, Morbini P, Cancellieri A, Damiani S, Cavazza A, Comin CE. Adenocarcinoma classification: patterns and prognosis. Pathologica 2018;110:5-11.

Travis WD. Pathology of lung cancer. Clin Chest Med 2011;32:669-692.

Denisenko TV, Budkevich IN, Zhivotovsky B. Cell death-based treatment of lung adenocarcinoma. Cell Death Dis 2018;9:117.

Liao YH, Li CI, Lin CC, Lin JG, Chiang JH, Li TC. Traditional Chinese medicine as adjunctive therapy improves the long-term survival of lung cancer patients. J Cancer Res Clin Oncol 2017;143:2425-2435.

Guo H, Liu JX, Xu L, Madebo T, Baak JP. Traditional Chinese medicine herbal treatment may have a relevant impact on the prognosis of patients with stage Ⅳ adenocarcinoma of the lung treated with platinum-based chemotherapy or combined targeted therapy and chemotherapy. Integr Cancer Ther 2011;10:127-137.

Li CL, Hsia TC, Li CH, Chen KJ, Yang YH, Yang ST. Adjunctive traditional Chinese medicine improves survival in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a nationwide, population-based cohort study. Integr Cancer Ther 2019;18:1534735419827079.

Jiao L, Xu J, Sun J, Chen Z, Gong Y, Bi L, et al. Chinese herbal medicine combined with EGFR-TKI in EGFR mutation-positive advanced pulmonary adenocarcinoma(CATLA): a multicenter, randomized, double-blind, placebo-controlled trial. Front Pharmacol 2019;10:732.

Zheng W, Wu J, Gu J, Weng H, Wang J, Wang T, et al. Modular characteristics and mechanism of action of herbs for endometriosis treatment in Chinese medicine: a data mining and network pharmacology-based identification. Front Pharmacol 2020;11:147.

Auyeung KK, Han QB, Ko JK. Astragalus membranaceus:a review of its protection against inflammation and gastrointestinal cancers. Am J Chin Med 2016;44:1-22.

Ma XQ, Shi Q, Duan JA, Dong TT, Tsim KW. Chemical analysis of Radix Astragali (Huangqi) in China: a comparison with its adulterants and seasonal variations. J Agric Food Chem 2002;50:4861-4866.

Wu TH, Yeh KY, Wang CH, Wang H, Li TL, Chan YL, et al. The combination of Astragalus membranaceus and Angelica sinensis inhibits lung cancer and cachexia through its immunomodulatory function. J Oncol 2019;2019:9206951.

Bamodu OA, Kuo KT, Wang CH, Huang WC, Wu ATH, Tsai JT, et al. Astragalus polysaccharides (PG2) enhances the M1 polarization of macrophages, functional maturation of dendritic cells, and T cell-mediated anticancer immune responses in patients with lung cancer. Nutrients 2019;11:2264.

Luo TT, Lu Y, Yan SK, Xiao X, Rong XL, Guo J. Network pharmacology in research of Chinese medicine formula:methodology, application and prospective. Chin J Integr Med 2020;26:72-80.

Huang J, Cheung F, Tan HY, Hong M, Wang N, Yang J, et al. Identification of the active compounds and significant pathways of Yinchenhao Decoction based on network pharmacology. Mol Med Rep 2017;16:4583-4592.

Boezio B, Audouze K, Ducrot P, Taboureau O. Network-based approaches in pharmacology. Mol Inform 2017;36:1700048.

Liu W, Fan Y, Tian C, Jin Y, Du S, Zeng P, et al. Deciphering the molecular targets and mechanisms of HGWD in the treatment of rheumatoid arthritis via network pharmacology and molecular docking. Evid Based Complement Alternat Med 2020;2020:7151634.

Ru J, Li P, Wang J, Zhou W, Li B, Huang C, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014;6:13.

UniProt: the universal protein knowledgebase. Nucleic Acids Res 2017;45:D158-D169.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13:2498-2504.

Wei C, Dong X, Lu H, Tong F, Chen L, Zhang R, et al. LPCAT1 promotes brain metastasis of lung adenocarcinoma by up-regulating PI3K/AKT/MYC pathway. J Exp Clin Cancer Res 2019;38:95.

Ming J, Zhu YJ, Ding ZY, Jing YD, Jiang GC. Interleukin 7 receptor activates PI3K/Akt/mTOR signaling pathway via downregulation of Beclin-1 in lung cancer. Molecular Carcinogenesis 2019;58:358-365.

Fabregat A, Sidiropoulos K, Garapati P, Gillespie M, Hausmann K, Haw R, et al. The reactome pathway knowledgebase. Nucleic Acids Res 2016;44:D481-D487.

Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 2017;19:649-658.

Berman H, Henrick K, Nakamura H. Announcing the worldwide Protein Data Bank. Nat Struct Biol 2003;10:980.

Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31:455-461.

Dong Y, Yang J, Yang L, Li P. Quercetin inhibits the proliferation and metastasis of human non-small cell lung cancer cell line: the key role of src-mediated fibroblast growth factor-inducible 14 (Fn14)/ nuclear factor kappa B(NF-κB) pathway. Med Sci Monit 2020;26:e920537.

Wu X, Zhou W, Wei Q, Chen P, Li Y. Cytoprotective effects of the medicinal herb Astragalus membranaceus on lipopolysaccharide-exposed cells. Mol Med Rep 2018;18:4321-4327.

Liao CH, Yong CY, Lai GM, Chow JM, Cheng CF, Fang CL, et al. Astragalus polysaccharide (PG2) suppresses macrophage migration inhibitory factor and aggressiveness of lung adenocarcinoma cells. Am J Chin Med 2020;48:1491-1509.

Fumarola C, Bonelli MA, Petronini PG, Alfieri RR. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol 2014;90:197-207.

Gu JJ, Qiao KS, Sun P, Chen P, Li Q. Study of EGCG induced apoptosis in lung cancer cells by inhibiting PI3K/Akt signaling pathway. Eur Rev Med Pharmacol Sci 2018;22:4557-4563.

Lee M, Theodoropoulou M, Graw J, Roncaroli F, Zatelli MC, Pellegata NS. Levels of p27 sensitize to dual PI3K/mTOR inhibition. Mol Cancer Ther 2011;10:1450-1459.

Zhou R, Xu L, Ye M, Liao M, Du H, Chen H. Formononetin inhibits migration and invasion of MDA-MB-231 and 4T1 breast cancer cells by suppressing MMP-2 and MMP-9 through PI3K/AKT signaling pathways. Horm Metab Res 2014;46:753-760.

Cao Y, Ruan Y, Shen T, Huang X, Li M, Yu W, et al. Astragalus polysaccharide suppresses doxorubicin-induced cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways. Oxid Med Cell Longev 2014;2014:674219.

Qian W, Cai X, Qian Q, Zhang W, Wang D. Astragaloside Ⅳ modulates TGF-β1-dependent epithelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. J Cell Mol Med 2018;22:4354-4365.

Uehara I, Tanaka N. Role of p53 in the regulation of the inflammatory tumor microenvironment and tumor suppression. Cancers (Basel) 2018;10:219.

Ahrendt SA, Hu Y, Buta M, McDermott MP, Benoit N, Yang SC, et al. p53 mutations and survival in stage Ⅰ non-small-cell lung cancer: results of a prospective study. J Natl Cancer Inst 2003;95:961-970.

Voisin L, Saba-El-Leil MK, Julien C, Frémin C, Meloche S. Genetic demonstration of a redundant role of extracellular signal-regulated kinase 1 (ERK1) and ERK2 mitogen-activated protein kinases in promoting fibroblast proliferation. Mol Cell Biol 2010;30:2918-2932.

Sun Y, Liu WZ, Liu T, Feng X, Yang N, Zhou HF. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res 2015;35:600-604.

Wang S, Shi J, Ye Z, Dong D, Yu D, Zhou M, et al. Predicting EGFR mutation status in lung adenocarcinoma on computed tomography image using deep learning. Eur Respir J 2019;53:1800986.

Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 2012;12:553-563.

Balsara BR, Pei J, Mitsuuchi Y, Page R, Klein-Szanto A, Wang H, et al. Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 2004;25:2053-2059.

Chen WS, Hou JN, Guo YB, Yang HL, Xie CM, Lin YC, et al. Bostrycin inhibits proliferation of human lung carcinoma A549 cells via downregulation of the PI3K/Akt pathway. J Exp Clin Cancer Res 2011;30:17.

Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 2004;431:525-526.

More>

Views

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

Therapeutic Mechanism of Kai Xin San on Alzheimer's Disease Based on Network Pharmacology and Experimental Validation

Mechanism of Fuzheng Kang'ai Formula Regulating Tumor Microenvironment in Non-Small Cell Lung Cancer

Network Pharmacology-Based Exploration of Synergistic Mechanism of Guanxin Ⅱ Formula (冠心Ⅱ号方) for Coronary Heart Disease

In Silico Screening of Potential Chinese Herbal Medicine Against COVID-19 by Targeting SARS-CoV-2 3CLpro and Angiotensin Converting Enzyme Ⅱ Using Molecular Docking

Chemical Composition, Pharmacological Effects and Clinical Applications of Cinobufacini

Related Author

No data

Related Institution

The Second Clinical Medical College, Guangzhou University of Chinese Medicine

Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine

Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology

Key Laboratory of Cosmetics Monitoring and Evaluation, State Drug Administration, Shenzhen Institute for Drug Control

The School of Basic Medical Sciences, Hubei University of Chinese Medicine

Address：1 Caochang, xiyuan, Beijing, People's Republic of China Postal code：100091
Tel：010-62886827, 62877592 Fax：010-62874291
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备05067934号-1 京公网安备11010802024621
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰

Mechanism of Key Ingredient of Astragalus membranaceus on Lung Adenocarcinoma via PI3K/AKT Signaling Clarified by Utilizing Network Pharmacology Approach and Experimental Validation

DOI：10.1007/s11655-022-3681-x

摘要

Abstract

关键词

Keywords

references