Tetrac downregulates β-catenin and HMGA2 to promote the effect of resveratrol in colon cancer

Endocr Relat Cancer. 2018 Mar;25(3):279-293. doi: 10.1530/ERC-17-0450. Epub 2017 Dec 18.

Abstract

The molecular pathogenesis of colorectal cancer encompasses the activation of several oncogenic signaling pathways that include the Wnt/β-catenin pathway and the overexpression of high mobility group protein A2 (HMGA2). Resveratrol - the polyphenolic phytoalexin - binds to integrin αvβ3 to induce apoptosis in cancer cells via cyclooxygenase 2 (COX-2) nuclear accumulation and p53-dependent apoptosis. Tetraiodothyroacetic acid (tetrac) is a de-aminated derivative of l-thyroxine (T4), which - in contrast to the parental hormone - impairs cancer cell proliferation. In the current study, we found that tetrac promoted resveratrol-induced anti-proliferation in colon cancer cell lines, in primary cultures of colon cancer cells, and in vivo The mechanisms implicated in this action involved the downregulation of nuclear β-catenin and HMGA2, which are capable of compromising resveratrol-induced COX-2 nuclear translocation. Silencing of either β-catenin or HMGA2 promoted resveratrol-induced anti-proliferation and COX-2 nuclear accumulation which is essential for integrin αvβ3-mediated-resveratrol-induced apoptosis in cancer cells. Concurrently, tetrac enhanced nuclear abundance of chibby family member 1, the nuclear β-catenin antagonist, which may further compromise the nuclear β-catenin-dependent gene expression and proliferation. Taken together, these results suggest that tetrac targets β-catenin and HMGA2 to promote resveratrol-induced-anti-proliferation in colon cancers, highlighting its potential in anti-cancer combination therapy.

Keywords: HMGA2; colorectal cancers; resveratrol; tetraiodothyroacetic acid; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / metabolism*
  • Down-Regulation / drug effects
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • HMGA2 Protein / genetics
  • HMGA2 Protein / metabolism*
  • Humans
  • Mice, Nude
  • Resveratrol / pharmacology*
  • Thyroxine / analogs & derivatives*
  • Thyroxine / pharmacology
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Antineoplastic Agents
  • HMGA2 Protein
  • beta Catenin
  • tetraiodothyroacetic acid
  • Resveratrol
  • Thyroxine