Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β

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.

Design, synthesis and biological evaluation of a novel colchicine-magnolol hybrid for inhibiting the growth of Lewis lung carcinoma in Vitro and in Vivo

“…Glycogen synthase kinase-3β (GSK3β) is a serine-threonine kinase that is responsible for promoting cancer cell survival, growth and proliferation ( Domoto et al, 2020 ). It has been well documented that aberrant GSK3β activity is firmly associated with multiple tumor-related diseases and that GSK3β is generally accepted as a potential anti-tumor target ( Bai et al, 2022 ; Fan et al, 2022 ; You et al, 2022 ). In light of this, we extended our effort to test the possibility that CMH may provide antiproliferative capacity through the direct inhibition of GSK3β enzyme activity.…”

Digitoxin inhibits ICC cell properties via the NF‑κB/ST6GAL1 signaling pathway

“…In recent years, researchers have been increasingly interested in exploring potential anticancer compounds from TCM. Nobiletin, a major component of Pericarpium Citri Reticulatae , could inhibit cholangiocarcinoma (CCA) proliferation by direct binding to GSK3β ( 21 ). β-elemene, a potent component found in turmeric from the Chinese herbal medicine Rhizoma Zedoariae , has the potential to halt the advancement of CCA through the reactivation of PCDH9 expression ( 22 ).…”

The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression

“…Through application of agonists, therapeutic targeting of clock components (NR1D1, NR1D2, and REV-ERBs) could be beneficial by stimulating apoptosis and impairing the proliferation of malignant cancer cells ( 48 ). Additionally, nobiletin is an activator of RORs ( 31 ) and exhibits antitumor effects on multiple cancer types by triggering tumor cell cycle arrest, apoptosis and ferroptosis ( 49 – 51 ); however, the effect of nobiletin on antitumor immune cell composition and immune responses is largely unknown. Here, we extend the effects of nobiletin, an antitumor immune activator, on melanoma.…”