Thyroid hormone and anti-apoptosis in tumor cells

Hung Yun Lin, Gennadi V. Glinsky, Shaker A. Mousa, Paul J. Davis

Research output: Contribution to journalReview article

23 Citations (Scopus)

Abstract

The principal secretory product of the thyroid gland, L-thyroxine (T4), is anti-apoptotic at physiological concentrations in a number of cancer cell lines. Among the mechanisms of anti-apoptosis activated by the hormone are interference with the Ser-15 phosphorylation (activation) of p53 and with TNFα/Fas-induced apoptosis. The hormone also decreases cellular abundance and activation of proteolytic caspases and of BAX and causes increased expression of X-linked inhibitor of apoptosis (XIAP). The anti-apoptotic effects of thyroid hormone largely are initiated at a cell surface thyroid hormone receptor on the extracellular domain of integrin αvβ3 that is amply expressed and activated in cancer cells. Tetraiodothyroacetic acid (tetrac) is a T4 derivative that, in a model of resveratrol-induced p53-dependent apoptosis in glioma cells, blocks the anti-apoptotic action of thyroid hormone, permitting specific serine phosphorylation of p53 and apoptosis to proceed. In a nanoparticulate formulation limiting its action to αvβ3, tetrac modulates integrin-dependent effects on gene expression in human cancer cell lines that include increased expression of a panel of pro-apoptotic genes and decreased transcription of defensive anti-apoptotic XIAP and MCL1 genes. By a variety of mechanisms, thyroid hormone (T4) is an endogenous anti-apoptotic factor that may oppose chemotherapy-induced apoptosis in αvβ3-expressing cancer cells. It is possible to decrease this anti-apoptotic activity pharmacologically by reducing circulating levels of T4 or by blocking effects of T4 that are initiated at αvβ3.

Original languageEnglish
Pages (from-to)14735-14743
Number of pages9
JournalOncotarget
Volume6
Issue number17
Publication statusPublished - 2015

Keywords

  • Apoptosis
  • Integrin αvβ3
  • Resveratrol
  • Tetrac
  • Thyroid hormone

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Lin, H. Y., Glinsky, G. V., Mousa, S. A., & Davis, P. J. (2015). Thyroid hormone and anti-apoptosis in tumor cells. Oncotarget, 6(17), 14735-14743.