Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β
Liping You, Jiacheng Lin, Zhuo Yu, Yihan Qian, Yuting Bi, Fang Wang, Lei Zhang, Chao Zheng, Jinghao Zhang, Wenxuan Li, Yaxuan Cai, Yueqiu Gao, Xiaoni Kong, Xuehua Sun
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 GSK3 was a direct target. Western blot and immunofluorescence confirmed that NBT reduced the phosphorylation of GSK3. The antiproliferative effect of NBT was intercepted in GSK3 knockdown CCA cells. The cellular thermal shift assay (CETSA) showed NBT directly bound to GSK3. 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 GSK3. We suggested that NBT might be a potential natural medicine in CCA treatment.