Taxifolin curbs NF-κB-mediated Wnt/β-catenin signaling via up-regulating Nrf2 pathway in experimental colon carcinogenesis

Biochimie. 2015 Dec;119:103-12. doi: 10.1016/j.biochi.2015.10.014. Epub 2015 Oct 19.

Abstract

Aberrations in homeostasis mechanisms including Nrf2, inflammatory, and Wnt/β-catenin signaling are the major causative factors implicated in colon cancer development. Hence blocking these pathways through natural interventions pave a new channel for colon cancer prevention. Earlier, we reported the chemopreventive effect of taxifolin (TAX) against colon carcinogenesis. In this study, we aimed to understand the ability of TAX, to modulate the Nrf2, inflammatory and Wnt/β-catenin cascades on 1, 2-dimethyl hydrazine (DMH)-induced mouse colon carcinogenesis. In addition, in silico molecular docking studies were performed to evaluate the binding affinity between TAX and target proteins (Nrf2, β-catenin, and TNF-α). We perceived that the increase of serum marker enzyme levels (CEA and LDH) and mast cell infiltration that occurs in the presence of DMH is inverted after TAX treatment. Immunoblot expression and docking analysis revealed that TAX could induce antioxidant response pathway, confirming the enhanced level of Nrf2 protein. It also inhibited NF-κB and Wnt signaling by down-regulating the levels of regulatory metabolites such as TNF-α, COX-2, β-catenin, and Cyclin-D1. Collectively, results of our hypothesis shown that TAX is an effective chemopreventive agent capable of modulating inflammatory, Wnt and antioxidant response pathway proteins in tumor microenvironment which explicating its anticancer property.

Keywords: Colon cancer; DMH; Docking; Nrf2; Taxifolin; Wnt/β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dimethylhydrazine / toxicity
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Antineoplastic Agents, Phytogenic / adverse effects
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Antioxidants / adverse effects
  • Antioxidants / chemistry
  • Antioxidants / pharmacokinetics
  • Antioxidants / therapeutic use*
  • Carcinogens / toxicity
  • Colon / drug effects
  • Colon / immunology
  • Colon / metabolism
  • Colon / pathology
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Humans
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Ligands
  • Male
  • Mast Cells / drug effects
  • Mast Cells / immunology
  • Mast Cells / metabolism
  • Mast Cells / pathology
  • Mice
  • Molecular Docking Simulation
  • NF-E2-Related Factor 2 / agonists*
  • NF-E2-Related Factor 2 / chemistry
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / chemistry
  • NF-kappa B / metabolism
  • Neoplasm Proteins / agonists
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism
  • Quercetin / adverse effects
  • Quercetin / analogs & derivatives*
  • Quercetin / chemistry
  • Quercetin / pharmacokinetics
  • Quercetin / therapeutic use
  • Random Allocation
  • Wnt Signaling Pathway / drug effects*
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / chemistry
  • beta Catenin / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents, Phytogenic
  • Antioxidants
  • CTNNB1 protein, mouse
  • Carcinogens
  • Ligands
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Neoplasm Proteins
  • Nfe2l2 protein, mouse
  • beta Catenin
  • Quercetin
  • taxifolin
  • 1,2-Dimethylhydrazine