Natural derivatives of curcumin attenuate the Wnt/beta-catenin pathway through down-regulation of the transcriptional coactivator p300.
Curcumin, a component of turmeric (Curcuma longa), has been reported to suppress beta-catenin response transcription (CRT), which is aberrantly activated in colorectal cancer. However, the effects of its natural analogs (demethoxycurcumin [DMC] and bisdemethoxycurcumin [BDMC]) and metabolite (tetrahydrocurcumin [THC]) on the Wnt/beta-catenin pathway have not been investigated. Here, we show that DMC and BDMC suppressed CRT that was activated by Wnt3a conditioned-medium (Wnt3a-CM) without altering the level of intracellular beta-catenin, and inhibited the growth of various colon cancer cells, with comparable potency to curcumin. Additionally, DMC and BDMC down-regulated p300, which is a positive regulator of the Wnt/beta-catenin pathway. Notably, THC also inhibited CRT and cell proliferation, but to a much lesser degree than curcumin, DMC, or BDMC, indicating that the conjugated bonds in the central seven-carbon chain of curcuminoids are essential for the inhibition of Wnt/beta-catenin pathway and the anti-proliferative activity of curcuminoids. Thus, our findings suggest that curcumin derivatives inhibit the Wnt/beta-catenin pathway by decreasing the amount of the transcriptional coactivator p300.
Ryu
Min-Jung
MJ
PharmacoGenomics Research Center, Inje University, Busan 614-735, Republic of Korea.
Cho
Munju
M
Song
Jie-Young
JY
Yun
Yeon-Sook
YS
Choi
Il-Whan
IW
Kim
Dong-Eun
DE
Park
Byeoung-Soo
BS
Oh
Sangtaek
S
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D036381:Diarylheptanoids; D015536:Down-Regulation; D006801:Humans; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D036381:Diarylheptanoids; D051153:Wnt Proteins; D051176:beta Catenin; C096277:tetrahydrocurcumin; C034786:bisdemethoxycurcumin; D050880:p300-CBP Transcription Factors; D003474:Curcumin; C050229:demethoxycurcumin