Figure 8From: Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways Schematic diagram showing possible mechanisms by which resveratrol (RSV) alters colon cancer cell kinetics. Obesity enhances insulin levels, which in turn elevates "bioactive IGF-1" levels by suppressing inhibitory IGF binding proteins (IGFBPs)-1 and -2. Activated IGF-1R phosphorylates a cascade of kinases PI3K, Akt and GSK3β. Phosphorylated and inactive GSK3β fails to form Axin/adenomatous polyposis coli (APC)/casein kinase 1 (CK1)/GSK3β destruction complex resulting in stabilization of cytosolic β-catenin and its subsequent nuclear translocation [reviewed in [64]]. In the nucleus, β-catenin binds to T-cell-factor 4 (TCF4) and stimulates the transcription of proliferative (e.g., cyclin D1) genes. The tumor suppressor p53, suppresses IGF-1R gene expression and phosphorylation. P53 attenuates IGF-1R transcription through its suppression of sp1, a critical mediator of IGF-1R transcription. Unphosphorylated, active FKHRL1 activates downstream target p27 and thus inhibiting cyclin D1 levels essential for cell cycle progression from G1 to S phase. Overall resveratrol suppresses IGF-1 induced colon cancer cell proliferation by A) downregulating IGF-1R levels, B) suppressing downstream IGF-1R/Akt and Wnt/β-catenin signaling C) activating p53 tumor suppressor protein, and by D) activation of FKHRL1/p27 signaling pathways.Back to article page