Garcinol inhibits proteasome and suppresses tumor growth via targeting RPN6
10.16438/j.0513-4870.2024-1024
- VernacularTitle:山竹醇靶向RPN6抑制蛋白酶体及抗肿瘤活性研究
- Author:
Ying YU
;
Xi-song KE
;
Xue ZHANG
- Publication Type:Research Article
- Keywords:
garcinol;
proteasome;
19S;
26S proteasome non-ATPase regulatory subunit 11;
tumor inhibition
- From:
Acta Pharmaceutica Sinica
2025;60(2):408-416
- CountryChina
- Language:Chinese
-
Abstract:
Garcinol, a benzenetriol compound extracted from Garcinia cambogia, has antitumor activity, however, its antitumor mechanism remains unclear. The aim of this study was to investigate the role and mechanism of garcinol as a novel potential proteasome inhibitor. We applied the drug affinity responsive target stability (DARTS) method coupled to mass spectrometry to determine the binding protein of garcinol; the proteasome activity assay was used to determine the effect of garcinol on its hydrolase activity; immunofluorescence and proximity ligation assay (PLA) were used to detect the effects of garcinol on ubiquitin and RPN6; and flow cytometry were used to determine the effects of garcinol on cell apoptosis; and the anti-cancer effect was studied in organoid models. The results showed that RPN6 was a direct binding protein of garcinol; garcinol inhibited the hydrolase activity of proteasome, and induced the accumulation and aggregation of ubiquitin protein, and its proteasomal inhibitory effect was dependent on RPN6; further studies showed that garcinol induced oligomerization of RPN6 and formation of granules in the nucleus; finally, it was verified that garcinol induced apoptosis of tumor cells, and inhibited the growth of organoids of Apcmin/+ small intestine mice. These results suggest that garcinol is a potential proteasome inhibitor, which inhibits proteasome activity by directly targeting RPN6 on proteasome 19S, which in turn induces cell apoptosis and inhibits tumor growth.
