Biological Mechanisms by Which Antiproliferative Actions of Resveratrol Are Minimized

Abstract

Preclinical and clinical studies have offered evidence for protective effects of various polyphenol-rich foods against cardiovascular diseases, neurodegenerative diseases, and cancers. Resveratrol is among the most widely studied polyphenols. However, the preventive and treatment effectiveness of resveratrol in cancer remain controversial because of certain limitations in existing studies. For example, studies of the activity of resveratrol against cancer cell lines in vitro have often been conducted at concentrations in the low μM to mM range, whereas dietary resveratrol or resveratrol-containing wine rarely achieve nM concentrations in the clinic. While the mechanisms underlying the failure of resveratrol to inhibit cancer growth in the intact organism are not fully understood, the interference by thyroid hormones with the anticancer activity of resveratrol have been well documented in both in vitro and xenograft studies. Thus, endogenous thyroid hormones may explain the failure of anticancer actions of resveratrol in intact animals, or in the clinic. In this review, mechanisms involved in resveratrol-induced antiproliferation and effects of thyroid hormones on these mechanisms are discussed.

Keywords: Nano-diamino-tetrac; antiproliferation; cancer; resveratrol; tetrac.

Figure 1

Thyroid hormone-induced interference with resveratrol-induced antiproliferation is blocked by tetrac and its nanoparticulate analog. Signal transduction pathways are involved in resveratrol-induced antiproliferation and thyroid hormone-mediated proliferation in cancer cells. Thyroid hormones, as T₄, in physiological concentrations, stimulate cancer cell proliferation via the hormone receptor site on integrin αvβ3, on the cell surface. Activated ERK1/2 (pERK1/2) is required for hormone-dependent cell proliferation, as shown by the ERK1/2 cascade inhibition by the selective inhibitor, PD98059. A distinct receptor for the stilbene is also present on integrin αvβ3, through which resveratrol activates ERK1/2 and induces nuclear cyclooxygenase (COX-2) accumulation. Phosphorylated ERK1/2, induced by resveratrol, also translocates into the cell nucleus and complexes with inducible COX-2 in resveratrol-treated cancer cells. This is an essential upstream step in the induction by resveratrol of p53 phosphorylation at Ser-15, and consequent p53-dependent antiproliferation. Blocking resveratrol-induced nuclear accumulation of COX-2 inhibits p53 phosphorylation and antiproliferation. T₄ inhibits the formation of the intranuclear pERK1/2-COX-2–p53 complex and consequent p53-dependent antiproliferation. The mechanism by which T₄ inhibits the generation of pERK1/2–COX-2–p53 nuclear complexes in resveratrol-exposed cells is not yet known. Although the activation of ERK1/2 induced by hormones and resveratrol is additive, the competition for pools of ERK1/2 between thyroid hormones and resveratrol appears to divert kinases to the cell proliferation pathway, and may play an important role in the inhibition by T₄ of resveratrol's pro-apoptotic action. Tetrac inhibits the expression of β-catenin and HMGA2, and NDAT inhibits the expression of RRM2, which is caused by resveratrol. In addition, both tetrac and NDAT activate the expression of Chibby, which binds to β-catenin and blocks its transcriptional activities. Thus, tetrac or NDAT may restore pro-apoptotic activity of resveratrol that has been lost due to the actions of endogenous thyroid hormones. Abbreviations: COX-2, cyclooxygenase-2; HMGA2, high mobility group AT-hook 2; tetrac/NDAT, tetraiodothyroacetic acid/nano–diamino–tetrac; RRM2, ribonucleoside diphosphate reductase subunit M2; Chibby, nuclear protein that directly binds to β-catenin and antagonizes its transcriptional activity; SUMO-2, small ubiquitin-related modifier-2.