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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2024

Open Access 01-12-2024 | NSCLC | Research

Shikonin reactivates TSGs GADD45B and PPP3CC to block NSCLC cell proliferation and migration through JNK/P38/MAPK signaling pathways

Authors: Yujia Zhao, Dan Wu, Zhenkai Fu, Wenna Liu, Yu Yao, Ying Liang

Published in: BMC Complementary Medicine and Therapies | Issue 1/2024

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Abstract

Background

Shikonin, a natural naphthoquinone compound extracted from the Chinese traditional herbal medicine “Lithospermum erythrorhizon”, possesses antitumor activity against various cancer types. Tumor-suppressor genes (TSGs) negatively regulate cell growth, proliferation, and differentiation, thereby inhibiting tumor formation. However, the molecular mechanism of action of shikonin on TSGs in non–small-cell lung cancer (NSCLC) remains unclear.

Methods

The inhibitory effect of shikonin on the proliferation and migration abilities of lung cancer cells were measured by Cell Counting Kit 8 (CCK8) and wound healing assays. The alteration of genes by shikonin treatment was detected by mRNA high-throughput sequencing and further confirmed by qPCR and western blotting experiments. The dominant functions of the upregulated genes were analyzed by GO and KEGG profiling.

Results

Shikonin inhibited the proliferation and migration of A549 and H1299 NSCLC cells in a dose-dependent manner. mRNA high-throughput sequencing revealed a total of 1794 upregulated genes in shikonin-treated NSCLC cells. Moreover, bioinformatic analysis of GO and KEGG profiling revealed that the up-regulated genes were mostly involved in the JNK/P38/MAPK signaling pathway, among which the expression of GADD45B and PPP3CC was significantly enhanced. Finally, we confirmed that GADD45B and PPP3CC were indeed upregulated in JNK/P38/MAPK pathway.

Conclusions

Taken together, these results suggested that shikonin might affect the expression of GADD45B and PPP3CC through the JNK/P38/MAPK pathway, therefore exerting an inhibitory effect on the proliferation and migration of cancer cells. To our knowledge, this is the first study reporting the role of shikonin in upregulating TSGs to activate the JNK/P38/MAPK signaling pathways in NSCLC.
Appendix
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Literature
1.
Campanella A, De Summa S, Tommasi S. Exhaled breath condensate biomarkers for Lung cancer. J Breath Res. 2019;13(4):044002.CrossRefPubMed
2.
Long Y, Wang C, Wang T, Li W, Dai W, Xie S, Tian Y, Liu M, Liu Y, Peng X, et al. High performance exhaled breath biomarkers for diagnosis of Lung cancer and potential biomarkers for classification of Lung cancer. J Breath Res. 2021;15(1):016017.CrossRefPubMed
3.
Rodak O, Peris-Diaz MD, Olbromski M, Podhorska-Okolow M, Dziegiel P. Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy. Cancers (Basel) 2021, 13(18).
4.
Mielgo-Rubio X, Uribelarrea EA, Cortes LQ, Moyano MS. Immunotherapy in non-small cell Lung cancer: update and new insights. J Clin Transl Res. 2021;7(1):1–21.PubMedPubMedCentral
5.
6.
Wei ZC, Chen J, Zuo F, Guo JL, Sun XD, Liu DM, Liu CH. Traditional Chinese Medicine has great potential as candidate Drugs for Lung cancer: a review. J Ethnopharmacol 2023, 300.
7.
Zhou Y, Hong T, Tong L, Liu W, Yang XT, Luo JH, Wang FL, Li J, Yan LJ. Astragalus polysaccharide combined with 10-hydroxycamptothecin inhibits Metastasis in non-small cell lung carcinoma cell lines via the MAP4K3/mTOR signaling pathway. Int J Mol Med. 2018;42(6):3093–104.PubMedPubMedCentral
8.
Ni MW, Wang HJ, Wang MM, Zhou W, Zhang JY, Wu JR, Zhang D, Jing ZW, Liu XK, Wu ZS et al. Investigation on the efficiency of Chinese herbal injections for treating non-small cell Lung Cancer with Vinorelbine and Cisplatin based on multidimensional bayesian network Meta-analysis. Front Pharmacol 2021, 11.
9.
Guo CJ, He JL, Song XMT, Tan L, Wang M, Jiang PD, Li YZ, XCao Z, Peng C. Pharmacological properties and derivatives of shikonin-A review in recent years. Pharmacol Res 2019, 149.
10.
Wang HN, Zuo JL. Shikonin Inhibits Non-Small-Cell Lung Cancer H1299 Cell Growth through Survivin Signaling Pathway. Anal Cell Pathol 2021, 2021.
11.
Boulos JC, Rahama M, Hegazy MF, Efferth T. Shikonin derivatives for cancer prevention and therapy. Cancer Lett. 2019;459:248–67.CrossRefPubMed
12.
Guo C, He J, Song X, Tan L, Wang M, Jiang P, Li Y, Cao Z, Peng C. Pharmacological properties and derivatives of shikonin-A review in recent years. Pharmacol Res. 2019;149:104463.CrossRefPubMed
13.
Zang F, Rao Y, Zhu X, Wu Z, Jiang H. Shikonin suppresses NEAT1 and Akt signaling in treating paclitaxel-resistant non-small cell of Lung cancer. Mol Med. 2020;26(1):28.CrossRefPubMedPubMedCentral
14.
Lipsick J. A history of Cancer Research: Tumor suppressor genes. Cold Spring Harb Perspect Biol 2020, 12(2).
15.
Wang LH, Wu CF, Rajasekaran N, Shin YK. Loss of Tumor suppressor gene function in Human Cancer: an overview. Cell Physiol Biochem. 2018;51(6):2647–93.CrossRefPubMed
16.
17.
Foster H, Ruiz EJ, Moore C, Stamp GWH, Nye EL, Li NN, Pan YH, He YL, Downward J, Behrens A. ATMIN is a Tumor suppressor gene in Lung Adenocarcinoma. Cancer Res. 2019;79(20):5159–66.CrossRefPubMedPubMedCentral
18.
Han CC, Li H, Ma ZF, Dong GZ, Wang QY, Wang SW, Fang PQ, Li X, Chen H, Liu TY et al. MIR99AHG is a noncoding Tumor suppressor gene in lung adenocarcinoma. Cell Death Dis 2021, 12(5).
19.
Lin ZK, Liu ZP, Tan XS, Li CH. SH3GL3 functions as a potent Tumor suppressor in Lung cancer in a SH3 domain dependent manner. Biochem Bioph Res Co. 2021;534:787–94.CrossRef
20.
Liang Y, Lu Q, Li W, Zhang D, Zhang F, Zou Q, Chen L, Tong Y, Liu M, Wang S, et al. Reactivation of tumour suppressor in Breast cancer by enhancer switching through NamiRNA network. Nucleic Acids Res. 2021;49(15):8556–72.CrossRefPubMedPubMedCentral
21.
Lee JH, Han SH, Kim YM, Kim SH, Yoo ES, Woo JS, Jung GH, Jung SH, Kim BS, Jung JY. Shikonin inhibits proliferation of Melanoma cells by MAPK pathway-mediated induction of apoptosis. Biosci Rep 2021, 41(1).
22.
Lohberger B, Glanzer D, Kaltenegger H, Eck N, Leithner A, Bauer R, Kretschmer N, Steinecker-Frohnwieser B. Shikonin derivatives cause apoptosis and cell cycle arrest in human chondrosarcoma cells via death receptors and MAPK regulation. BMC Cancer. 2022;22(1):758.CrossRefPubMedPubMedCentral
23.
Zhao M, Sun J, Zhao Z. TSGene: a web resource for Tumor suppressor genes. Nucleic Acids Res. 2013;41(Database issue):D970–976.CrossRefPubMed
24.
Zhao M, Kim P, Mitra R, Zhao J, Zhao Z. TSGene 2.0: an updated literature-based knowledgebase for Tumor suppressor genes. Nucleic Acids Res. 2016;44(D1):D1023–1031.CrossRefPubMed
25.
Chandrashekar DS, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, Netto GJ, Qin ZS, Kumar S, Manne U, et al. UALCAN: an update to the integrated cancer data analysis platform. Neoplasia. 2022;25:18–27.CrossRefPubMedPubMedCentral
26.
Wang Q, Wu WH, Gao Z, Li KW, Peng SR, Fan HY, Xie ZQ, Guo ZH, Huang H. GADD45B is a potential diagnostic and therapeutic target gene in chemotherapy-resistant Prostate Cancer. Front Cell Dev Biol 2021, 9.
27.
Anastasiadou E, Messina E, Sanavia T, Labruna V, Ceccarelli S, Megiorni F, Gerini G, Pontecorvi P, Camero S, Perniola G et al. Calcineurin Gamma Catalytic Subunit PPP3CC inhibition by miR-200c-3p affects apoptosis in epithelial Ovarian Cancer. Genes (Basel) 2021, 12(9).
28.
Sun Q, Gong T, Liu M, Ren S, Yang H, Zeng S, Zhao H, Chen L, Ming T, Meng X, et al. Shikonin, a naphthalene ingredient: therapeutic actions, pharmacokinetics, toxicology, clinical trials and pharmaceutical researches. Phytomedicine. 2022;94:153805.CrossRefPubMed
29.
Gao L, Wu ZX, Assaraf YG, Chen ZS, Wang L. Overcoming anti-cancer drug resistance via restoration of Tumor suppressor gene function. Drug Resist Updat. 2021;57:100770.CrossRefPubMed
30.
31.
Chen JL, Miller DT, Schmidt LS, Malkin D, Korf BR, Eng C, Kwiatkowski DJ, Giannikou K. Mosaicism in Tumor suppressor gene syndromes: prevalence, diagnostic strategies, and transmission risk. Annu Rev Genomics Hum Genet. 2022;23:331–61.CrossRefPubMed
32.
Gong LQ, Cai LQ, Li GD, Cai J, Yi XQ. GADD45B facilitates Metastasis of Ovarian Cancer through epithelial-mesenchymal transition. Oncotargets Ther. 2021;14:255–69.CrossRef
33.
Barros MC, de Mello JBH, Marchi FA, Pinto CAL, da Silva IC, Damasceno PKF, Soares MBP, Kowalski LP, Rogatto SR. GADD45B transcript is a prognostic marker in papillary thyroid carcinoma patients treated with total thyroidectomy and Radioiodine Therapy. Front Endocrinol 2020, 11.
34.
Do H, Kim D, Kang J, Son B, Seo D, Youn H, Youn B, Kim W. TFAP2C increases cell proliferation by downregulating GADD45B and PMAIP1 in non-small cell Lung cancer cells. Biol Res. 2019;52(1):35.CrossRefPubMedPubMedCentral
35.
Wang H, Zhao S, Chen B, Fu C, Dang Y, Fang P, Wang J, Wang N, Liu L. Repression of the expression of PPP3CC by ZEB1 confers activation of NF-kappaB and contributes to invasion and growth in glioma cells. Jpn J Clin Oncol. 2018;48(2):175–83.CrossRefPubMed
36.
Nettersheim D, Jostes S, Fabry M, Honecker F, Schumacher V, Kirfel J, Kristiansen G, Schorle H. A signaling cascade including ARID1A, GADD45B and DUSP1 induces apoptosis and affects the cell cycle of germ cell cancers after romidepsin treatment. Oncotarget. 2016;7(46):74931–46.CrossRefPubMedPubMedCentral
Metadata
Title
Shikonin reactivates TSGs GADD45B and PPP3CC to block NSCLC cell proliferation and migration through JNK/P38/MAPK signaling pathways
Authors
Yujia Zhao
Dan Wu
Zhenkai Fu
Wenna Liu
Yu Yao
Ying Liang
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2024
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-023-04306-z

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