Murrayafoline A attenuates the Wnt/beta-catenin pathway by promoting the degradation of intracellular beta-catenin proteins.
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.
Choi
Hyuk
H
PharmacoGenomics Research Center, Inje University, Busan 614-735, Republic of Korea.
Gwak
Jungsug
J
Cho
Munju
M
Ryu
Min-Jung
MJ
Lee
Jee-Hyun
JH
Kim
Sang Kyum
SK
Kim
Young Ho
YH
Lee
Gye Won
GW
Yun
Mi-Young
MY
Cuong
Nguyen Manh
NM
Shin
Jae-Gook
JG
Song
Gyu-Yong
GY
Oh
Sangtaek
S
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
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