Natural derivatives of curcumin attenuate the Wnt/β-catenin pathway through down-regulation of the transcriptional coactivator p300

doi:10.1016/j.bbrc.2008.10.171

Biochemical and Biophysical Research Communications

Volume 377, Issue 4, 26 December 2008, Pages 1304-1308

https://doi.org/10.1016/j.bbrc.2008.10.171 Get rights and content

Abstract

Curcumin, a component of turmeric (Curcuma longa), has been reported to suppress β-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/β-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 β-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/β-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/β-catenin pathway and the anti-proliferative activity of curcuminoids. Thus, our findings suggest that curcumin derivatives inhibit the Wnt/β-catenin pathway by decreasing the amount of the transcriptional coactivator p300.

Section snippets

Materials and methods

Chemicals and plasmids. Curcumin, DMC, BDMC, and THC were prepared from the dried rhizomes of C. longa as described previously [20] and were then dissolved in DMSO. Human Frizzled-1 (hFz-1) cDNA was cloned as described previously [21]. The pTOPFlash and pFOPFlash reporter plasmids were obtained from Upstate Biotechnology (Lake Placid, NY, USA). Secreted alkaline phosphatase (SEAP) reporter plasmid was constructed by insertion of five copies TCF/LEF-binding site (AAGATCAAAGGGGGT) to E1b minimal

Curcumin derivatives inhibit the Wnt/β-catenin pathway

Curcumin has two methoxy groups at its ortho position, whereas DMC contains only one and BDMC has none (Fig. 1). In comparison, THC possesses two methoxy groups, but lacks the conjugated bond in the central seven-carbon chain (Fig. 1). We evaluated the ability of curcumin, its natural analogs, DMC and BDMC, and THC to inhibit the Wnt/β-catenin pathway using HEK293 reporter cells stably transfected with a synthetic β-catenin/Tcf-dependent firefly luciferase (FL) reporter and hFz-1 expression

Acknowledgments

This work was supported by the Korea Institute of Science & Technology Evaluation and Planning (KISTEP) and Ministry of Science & Technology (MOST), Korean government, through its National Nuclear Technology Program (S. Oh) and by a 2006 Inje University Research Grant (I.-W. Choi).

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Natural derivatives of curcumin attenuate the Wnt/β-catenin pathway through down-regulation of the transcriptional coactivator p300

Abstract

Section snippets

Materials and methods

Curcumin derivatives inhibit the Wnt/β-catenin pathway

Acknowledgments

Cell

Pathology

Cancer Lett.

J. Biol. Chem.

FEBS Lett.