title: Murrayafoline A attenuates the Wnt/beta-catenin pathway by promoting the degradation of intracellular beta-catenin proteins.
abstract: Molecular lesions in Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) occur frequently during the development of colon cancer. To identify small molecules that suppress CRT, we screened natural compounds in a cell-based assay for detection of TOPFalsh reporter activity. Murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa, antagonized CRT that was stimulated by Wnt3a-conditioned medium (Wnt3a-CM) or LiCl, an inhibitor of glycogen synthase kinase-3beta (GSK-3beta), and promoted the degradation of intracellular beta-catenin without altering its N-terminal phosphorylation at the Ser33/37 residues, marking it for proteasomal degradation, or the expression of Siah-1, an E3 ubiquitin ligase. Murrayafoline A repressed the expression of cyclin D1 and c-myc, which is known beta-catenin/T cell factor (TCF)-dependent genes and thus inhibited the proliferation of various colon cancer cells. These findings indicate that murrayafoline A may be a potential chemotherapeutic agent for use in the treatment of colon cancer.
authors: PharmacoGenomics Research Center, Inje University, Busan 614-735, Republic of Korea.
authors: Hyuk
authors: H
authors: Choi
authors: Jungsug
authors: J
authors: Gwak
authors: Munju
authors: M
authors: Cho
authors: Min-Jung
authors: MJ
authors: Ryu
authors: Jee-Hyun
authors: JH
authors: Lee
authors: Sang Kyum
authors: SK
authors: Kim
authors: Young Ho
authors: YH
authors: Kim
authors: Gye Won
authors: GW
authors: Lee
authors: Mi-Young
authors: MY
authors: Yun
authors: Nguyen Manh
authors: NM
authors: Cuong
authors: Jae-Gook
authors: JG
authors: Shin
authors: Gyu-Yong
authors: GY
authors: Song
authors: Sangtaek
authors: S
authors: Oh
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D002227:Carbazoles; D009687:Nuclear Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C443728:murrayafoline A; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins