Isoreserpine promotes beta-catenin degradation via Siah-1 up-regulation in HCT116 colon cancer cells.
Aberrant accumulation of intracellular beta-catenin in intestinal epithelial cells is a frequent early event during the development of colon cancer. To identify small molecules that decrease the level of intracellular beta-catenin, we performed cell-based chemical screening using genetically engineered HEK293 reporter cells to detect compounds that inhibit TOPFlash reporter activity, which was stimulated by Wnt3a-conditioned medium. We found that isoreserpine promoted the degradation of intracellular beta-catenin by up-regulation of Siah-1 in HEK293 and HCT116 colon cancer cells. Moreover, isoreserpine repressed the expression of beta-catenin/T-cell factor (TCF)-dependent genes, such as cyclin D1 and c-myc, resulting in the suppression of HCT116 cell proliferation. Our findings suggest that isoreserpine can potentially be used as a chemotherapeutic agent against colon cancer.
Gwak
Jungsug
J
PharmacoGenomics Research Center, Inje University, Busan, Republic of Korea.
Song
Taeyun
T
Song
Jie-Young
JY
Yun
Yeon-Sook
YS
Choi
Il-Whan
IW
Jeong
Yongsu
Y
Shin
Jae-Gook
JG
Oh
Sangtaek
S
D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D012110:Reserpine / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013237:Stereoisomerism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D009687:Nuclear Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D012110:Reserpine; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins