title: Ursolic acid and its natural derivative corosolic acid suppress the proliferation of APC-mutated colon cancer cells through promotion of β-catenin degradation.
abstract: Ursolic acid (UA) and corosolic acid (CA), naturally occurring pentacyclic triterpene acids, exhibit antiproliferative activities against various cancer cells, but a clear chemopreventive mechanism of these triterpenoids in colon cancer cells remains to be answered. Here we used a cell-based reporter system for detection of β-catenin response transcription (CRT) to identify UA as an antagonist of the Wnt/β-catenin pathway. UA promoted the degradation of intracellular β-catenin that was accompanied by its N-terminal phosphorylation at Ser33/37/Thr41 residues, marking it for proteasomal degradation. Consistently, UA down-regulated the intracellular β-catenin level in colon cancer cells with inactivating mutations of adenomatous polyposis coli (APC). In addition, UA repressed the expression of β-catenin/T-cell factor (TCF)-dependent genes, thereby inhibiting cell proliferation in colon cancer cells. The functional group analysis revealed that the major structural requirements for UA-mediated β-catenin degradation are a carboxyl group at position 17 and a methyl group at position 19. Notably, CA (2α-hydroxyursolic acid) was also found to decrease the level of intracellular β-catenin and to suppress the growth of APC-mutated colon cancer cells. Our findings suggest that UA and CA exert their anticancer activities against colon cancer cells by promoting the N-terminal phosphorylation and subsequent proteasomal degradation of β-catenin.
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Republic of Korea.
authors.forename: Joo-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Gyu-Yong
authors.initials: GY
authors.lastname: Song
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Dong-Eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: Department of Bio and Nanochemistry, Kookmin University, Seoul 136-702, Republic of Korea.
authors.forename: Yong-Joo
authors.initials: YJ
authors.lastname: Jeong
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Republic of Korea. Electronic address: ohsa@kookmin.ac.kr.
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D017491:Genes, APC; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D009154:Mutation; D010766:Phosphorylation; D014315:Triterpenes / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism*; D000097245:Ursolic Acid
chemical_list: D014315:Triterpenes; D051176:beta Catenin; D000097245:Ursolic Acid; C113861:corosolic acid
keywords: Colon cancer; Corosolic acid; Protein degradation; Ursolic acid; Wnt/β-catenin signaling