Int J Biol Sci 2022; 18(15):5698-5712. doi:10.7150/ijbs.78345 This issue Cite

Research Paper

Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β

Liping You1,2*, Jiacheng Lin2*, Zhuo Yu1*, Yihan Qian2, Yuting Bi1,2, Fang Wang2, Lei Zhang1, Chao Zheng1, Jinghao Zhang1, Wenxuan Li1,2, Yaxuan Cai3, Yueqiu Gao1✉, Xiaoni Kong2✉, Xuehua Sun1✉

1. Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.
2. Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.
3. Shanghai experimental school, Shanghai, China.
*These authors contributed equally to this work.

Citation:
You L, Lin J, Yu Z, Qian Y, Bi Y, Wang F, Zhang L, Zheng C, Zhang J, Li W, Cai Y, Gao Y, Kong X, Sun X. Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β. Int J Biol Sci 2022; 18(15):5698-5712. doi:10.7150/ijbs.78345. https://www.ijbs.com/v18p5698.htm
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Abstract

Graphic abstract

Background: Cholangiocarcinoma (CCA) is a type of hepatobiliary cancer characterized by uncontrolled cell proliferation, with a poor prognosis and high mortality. Nobiletin (NBT) is a promising anti-tumor compound derived from the peels of oranges and other citrus plants, citrus plant. But the effect of NBT on CCA remains unknown.

Results: Our data showed that NBT suppressed CCA cell proliferation in vitro and in vivo. Colony formation and Edu assay indicated that NBT inhibited cell proliferation. Cell cycle analysis showed that NBT arrested the cell cycle in G0/G1 phase. Target prediction showed that GSK3β was a direct target. Western blot and immunofluorescence confirmed that NBT reduced the phosphorylation of GSK3β. The antiproliferative effect of NBT was intercepted in GSK3β knockdown CCA cells. The cellular thermal shift assay (CETSA) showed NBT directly bound to GSK3β. Finally, NBT showed an anti-proliferative effect in tumor-bearing mice with no hepatotoxicity.

Conclusion: NBT could inhibit CCA proliferation, and the pharmacological activity of NBT in CCA was attributed to its direct binding to GSK3β. We suggested that NBT might be a potential natural medicine in CCA treatment.

Keywords: Nobiletin, Cholangiocarcinoma, GSK3β, β-catenin, natural medicine


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APA
You, L., Lin, J., Yu, Z., Qian, Y., Bi, Y., Wang, F., Zhang, L., Zheng, C., Zhang, J., Li, W., Cai, Y., Gao, Y., Kong, X., Sun, X. (2022). Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β. International Journal of Biological Sciences, 18(15), 5698-5712. https://doi.org/10.7150/ijbs.78345.

ACS
You, L.; Lin, J.; Yu, Z.; Qian, Y.; Bi, Y.; Wang, F.; Zhang, L.; Zheng, C.; Zhang, J.; Li, W.; Cai, Y.; Gao, Y.; Kong, X.; Sun, X. Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β. Int. J. Biol. Sci. 2022, 18 (15), 5698-5712. DOI: 10.7150/ijbs.78345.

NLM
You L, Lin J, Yu Z, Qian Y, Bi Y, Wang F, Zhang L, Zheng C, Zhang J, Li W, Cai Y, Gao Y, Kong X, Sun X. Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β. Int J Biol Sci 2022; 18(15):5698-5712. doi:10.7150/ijbs.78345. https://www.ijbs.com/v18p5698.htm

CSE
You L, Lin J, Yu Z, Qian Y, Bi Y, Wang F, Zhang L, Zheng C, Zhang J, Li W, Cai Y, Gao Y, Kong X, Sun X. 2022. Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β. Int J Biol Sci. 18(15):5698-5712.

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