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

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

Author information

1
PhD Program for Cancer Molecular Biology and Drug DiscoveryCollege of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
2
PhD Program for Cancer Molecular Biology and Drug DiscoveryCollege of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
3
Taipei Cancer CenterTaipei Medical University, Taipei, Taiwan.
4
Center for Teeth Bank and Dental Stem Cell Technology and School of DentistryCollege of Oral Medicine, Taipei Medical University, Taipei, Taiwan.
5
School of PharmacyCollege of Pharmacy, Taipei Medical University, Taipei, Taiwan.
6
Center for Immunology and Microbial DiseasesAlbany Medical College, Albany, New York, USA.
7
Integrated LaboratoryCenter of Translational Medicine, Core Facility, Taipei Medical University, Taipei, Taiwan.
8
Department of BiologyUniversity Tor Vergata, Rome, Italy.
9
Department of SciencesUniversity Roma Tre, Rome, Italy.
10
Department of DentistryTaipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan.
11
Laboratory of Chemical Biology and Medicinal ChemistryInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
12
Doctoral Degree Program in Marine BiotechnologyNational Sun Yat-Sen University, Taipei, Taiwan.
13
Pharmaceutical Research InstituteAlbany College of Pharmacy and Health Sciences, Albany, New York, USA.
14
PhD Program for Cancer Molecular Biology and Drug DiscoveryCollege of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan linhy@tmu.edu.tw.
15
Traditional Herbal Medicine Research Center of Taipei Medical University HospitalTaipei Medical University, Taipei, Taiwan.
16
Department of MedicineAlbany Medical College, Albany, New York, USA.

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

PMID:
29255096
DOI:
10.1530/ERC-17-0450

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