Juglone Inhibits Tumor Metastasis by Regulating Stemness Characteristics and the Epithelial-to-Mesenchymal Transition in Cancer Cells both in Vitro and in Vivo

Juglone Inhibits Tumor Metastasis by Regulating Stemness Characteristics and the Epithelial-to-Mesenchymal Transition in Cancer Cells both in Vitro and in Vivo

Chendan Zou^1,2,†, Yuan Yu^1,†, Hefei Wang^1,†, Cedric Matunda^1,3, Shuang Ding¹, Linlin Wang¹, Xianwei Chen¹, Yunting Le¹, Jianfeng Jin⁴, Xu Gao^1,2,5,*, Chaoxia Zou^1,2,5,*

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¹ Department of Biochemistry and Molecular Biology, Harbin Medical University, 150081 Harbin, Heilongjiang, China

² Translational Medicine Research and Cooperation Center of Northern China, 150081 Harbin, Heilongjiang, China

³ Department of Biochemistry and Biotechnology, Technical University of Kenya, 999070 Nairobi, Kenya

⁴ Department of Biochemistry and Molecular Biology, Hainan Medical University, 571199 Haikou, Hainan, China

⁵ Academy of Medicine Sciences, 150081 Harbin, Heilongjiang, China

^*Correspondence: Gaoxu_671227@163.com (Xu Gao); Zouchaoxia006@126.com (Chaoxia Zou)
^†These authors contributed equally.

Front. Biosci. (Landmark Ed) 2023, 28(2), 26; https://doi.org/10.31083/j.fbl2802026

Submitted: 10 September 2022 | Revised: 6 December 2022 | Accepted: 12 December 2022 | Published: 8 February 2023

This is an open access article under the CC BY 4.0 license.

Abstract

Background: The stemness characteristics of cancer cells, such as self-renewal and tumorigenicity, are considered to be responsible, in part, for tumor metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in promoting both stemness and tumor metastasis. Although the traditional medicine juglone is thought to play an anticancer role by affecting cell cycle arrest, induction of apoptosis, and immune regulation, a potential function of juglone in regulating cancer cell stemness characteristics remains unknown. Methods: In the present study, tumor sphere formation assay and limiting dilution cell transplantation assays were performed to assess the function of juglone in regulating maintenance of cancer cell stemness characteristics. EMT of cancer cells was assessed by western blot and transwell assay in vitro, and a liver metastasis model was also performed to demonstrate the effect of juglone on colorectal cancer cells in vivo. Results: Data gathered indicates juglone inhibits stemness characteristics and EMT in cancer cells. Furthermore, we verified that metastasis was suppressed by juglone treatment. We also observed that these effects were, in part, achieved by inhibiting Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1). Conclusions: These results indicate that juglone inhibits maintenance of stemness characteristics and metastasis in cancer cells.

Keywords

juglone

stemness

epithelial-to-mesenchymal transition (EMT)

Pin1

metastasis

tumorigenicity

Funding

HMUMIF-21025/Heilongjiang Touyan Innovation Team Program, HMU Marshal Initiative Funding

LBH-Z21178/Heilongjiang Postdoctoral Science Foundation

LPHGRD2022-004/Open Project Program of Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education

2019RC203/Hainan Provincial Natural Science Foundation of China

Figures

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Fig. 1.

Juglone suppresses the self-renewal ability of different cancer cells. (A,B) MCF7 and HCT116 cells were treated with indicated doses of juglone and cultured in serum-free media under non-adherent conditions for 7 days. Scale bar, 100 $\mu{}$ m. (C,D) A colony formation assay was performed, culture plates were stained with crystal violet. *p $<$ 0.05, **p $<$ 0.01, ***p $<$ 0.001.

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