Thyroid hormone and anti-apoptosis in tumor cells

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

PDF  |  HTML  |  How to cite

Oncotarget. 2015; 6:14735-14743. https://doi.org/10.18632/oncotarget.4023

Metrics: PDF 2845 views  |   HTML 2688 views  |   ?  


Hung-Yun Lin1,2, Gennadi V. Glinsky3, Shaker A. Mousa4, Paul J. Davis4,5

1PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei, Taiwan

2Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

3Stanford University, Palo Alto, CA, USA

4Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA

5Department of Medicine, Albany Medical College, Albany, NY, USA

Correspondence to:

Paul J. Davis, e-mail: [email protected]

Keywords: thyroid hormone, integrin αvβ3, resveratrol, tetrac, apoptosis

Received: March 23, 2015     Accepted: May 11, 2015     Published: May 23, 2015


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 4023