Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

Abstract

Resveratrol is a bioflavonoid which is known to inhibit cell proliferation and induce apoptosis in cancer cell lines at concentrations above 50uM. It also has colon cancer prevention activity in mouse models and possibly in humans. We have examined the effects of low concentrations of resveratrol on a specific signaling pathway, the Wnt pathway, which is activated in over 85% of sporadic colon cancers. Two colon cancer (HT29 and RKO) and one normal mucosa-derived (NCM460) cell lines were utilized. Cell proliferation was not affected by resveratrol at ≤40uM for HT29 and NCM460 and <20uM for RKO though Wnt signal throughput, as measured by a reporter construct, was reduced in RKO and NCM460 at concentrations as low as 10uM (p<0.001). This effect was most easily appreciated following Wnt pathway stimulation with Wnt3a conditioned medium and LEF1 or LEF1/ β-catenin transfection. Resveratrol did not inhibit Wnt throughput in mutationally activated HT29. Low concentrations of resveratrol significantly decreased the amount and proportion of β-catenin in the nucleus in RKO (p=0.002) and reduced the expression of lgs and pygoI, regulators of β-catenin localization in all cells lines. Thus, at low concentrations, in the absence of effects on cell proliferation, resveratrol significantly inhibits Wnt signaling in colon-derived cells which do not have a basally activated Wnt pathway. This inhibitory effect may be due in part to regulation of intracellular β-catenin localization.

Phase I Randomized, Double-Blind Pilot Study of Micronized Resveratrol (SRT501) in Patients with Hepatic Metastases—Safety, Pharmacokinetics, and Pharmacodynamics

“…Mechanisms by which low concentrations of resveratrol have been observed to induce apoptotic and antiproliferative effect in vitro include induction of Fas redistribution and its association with the deathinducing signaling complex (DISC; ref. 20) and via inhibition of Wnt signaling and subsequent decrease in nuclear b-catenin localization (21). In a preclinical model of diethylnitrosamine-initiated hepatocarcinogenesis, significant resveratrol-mediated apoptosis likely resulted from increased Bax expression and consequent increase in the Bax to Bcl-2 ratio (22).…”

Molecular mechanisms for chemoprevention of colorectal cancer by natural dietary compounds

“…Inhibits Wnt signaling and regulation of intracellular b-catenin localization in colon-derived cells [45] Pterostilbene Reduces cell proliferation by decreasing c-Myc and cyclin D1 expression, suppresses iNOS and COX-2 expression through downregulating p38 cascade [46] Inhibits AOM-induced colonic carcinogenesis through downregulation of Wnt/b-catenin, EGFR, PI3K/Akt, NF-kB signaling, and inflammatory gene expression [47,48] Mol. Nutr.…”

Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach

“…COX-2 activity enhances the cross talk between the membrane tyrosine kinases c-Met and EGFR, resulting in nuclear accumulation of ␤-catenin; however, the precise mechanisms are unclear. Other known compounds that also may possess druglike activity against cancer through regulation of ␤-catenin include the antidiabetic harmine, the wine antioxidant resveratrol, and the spice curcumin (18,21,53,55).…”