Cytotoxic activity of aeroplysinin-1 against colon cancer cells by promoting β-catenin degradation.
An aberrant accumulation of β-catenin in intestinal epithelial cells is relevant to the development and progression of colon cancer and is thus a potential target for the development of therapeutics for this malignancy. Here, we used cell-based natural compound screening with genetically engineered HEK293 reporter cells to identify aeroplysinin-1, a brominated tyrosine derivative originated from marine sponges, as an inhibitor of Wnt/β-catenin signaling. Aeroplysinin-1 suppressed the β-catenin response transcription that was activated by Wnt3a-conditioned medium or 6-bromoindirubin-3'-oxime (an inhibitor of glycogen synthase kinase-3β) by promoting the proteasomal degradation of intracellular β-catenin. Consistently, aeroplysinin-1 decreased the amount of intracellular β-catenin and repressed the expression of β-catenin/T-cell factor-dependent genes, thereby inhibiting the proliferation of colon cancer cells. In addition, apoptosis was elicited by aeroplysinin-1, as indicated by the increase in the population of Annexin V-FITC stained cells and caspase-3/7 activities in DLD-1 colon cancer cells. These findings indicate that aeroplysinin-1 exerts its antiproliferative activity by attenuating Wnt/β-catenin signaling and may have potential as a chemopreventive agent for human colon cancer.
Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea.
Seoyoung
S
Park
Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea.
Joo-Hyun
JH
Kim
Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea.
Jung Eun
JE
Kim
College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
Gyu-Yong
GY
Song
College of Pharmacy, Yanbian University, Yanji 133002, China.
Wei
W
Zhou
Cancer Genomics Branch National Cancer Center, Goyang 10408, Republic of Korea.
Sung-Ho
SH
Goh
College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address: mkna@cnu.ac.kr.
MinKyun
M
Na
Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea. Electronic address: ohsa@kookmin.ac.kr.
Sangtaek
S
Oh
D000097:Acetonitriles / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053138:Cyclohexenes / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000097:Acetonitriles; D053138:Cyclohexenes; D012333:RNA, Messenger; D051176:beta Catenin; C042151:aeroplysinin I; D053148:Caspase 3
Aeroplysinin-1; Colon cancer; Protein degradation; Wnt/β-catenin signaling