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Thyroid Hormone, Cancer, and Apoptosis

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Thyroid hormones play important roles in regulating normal metabolism, development, and growth. They also stimulate cancer cell proliferation. Their metabolic and developmental effects and growth effects in normal tissues are mediated primarily by nuclear hormone receptors. A cell surface receptor for the hormone on integrin αvβ3 is the initiation site for effects on tumor cells. Clinical hypothyroidism may retard cancer growth, and hyperthyroidism was recently linked to the prevalence of certain cancers. Local levels of thyroid hormones are controlled through activation and deactivation of iodothyronine deiodinases in different organs. The relative activities of different deiodinases that exist in tissues or organs also affect the progression and development of specific types of cancers. In this review, the effects of thyroid hormone on signaling pathways in breast, brain, liver, thyroid, and colon cancers are discussed. The importance of nuclear thyroid hormone receptor isoforms and of the hormone receptor on the extracellular domain of integrin αvβ3 as potential cancer risk factors and therapeutic targets are addressed. We analyze the intracellular signaling pathways activated by thyroid hormones in cancer progression in hyperthyroidism or at physiological concentrations in the euthyroid state. Determining how to utilize the deaminated thyroid hormone analog (tetrac), and its nanoparticulate derivative to reduce risks of cancer progression, enhance therapeutic outcomes, and prevent cancer recurrence is also deliberated. © 2016 American Physiological Society. Compr Physiol 6:1221‐1237, 2016.

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Figure 1. Figure 1. Schematic diagram of the proposed mechanisms by which thyroid hormone regulates cancer cell proliferation. In one mechanism, T4 penetrates cell membrane via active transporters and is converted to T3 by a deiodinase (D1 or D2). When T3 binds to a nuclear thyroid hormone receptor α1 (TRα1), β‐catenin abundance is enhanced and the protein translocates to the nucleus, where it stimulates cell proliferation. When T3 binds to TRβ1, the genomic consequences are normal thyroid hormone‐dependent biological activities, which also shows antiproliferative effect in cancer cells. However, the antiproliferative effect of TRβ1 is reduced by overexpression of D3 induced by TRα‐enhanced β‐catenin‐dependent mechanisms. In a mechanism that begins at the cell surface, T4 and, less avidly, T3 bind to integrin αvβ3 and activate ERK1/2 phosphorylation, and nongenomically stimulate cancer cell proliferation. When T3 binds to integrin αvβ3, it activates not only ERK1/2 by phosphorylation, but also activates Akt by triggering PI3K phosphorylation. Thus, Akt enhances HIF‐1α expression and then stimulates cancer cell metastasis. The opened‐boxes represent the normal signal pathways, however, colored‐boxes represent signals involved in the progression of cancers.

Figure 1. Schematic diagram of the proposed mechanisms by which thyroid hormone regulates cancer cell proliferation. In one mechanism, T4 penetrates cell membrane via active transporters and is converted to T3 by a deiodinase (D1 or D2). When T3 binds to a nuclear thyroid hormone receptor α1 (TRα1), β‐catenin abundance is enhanced and the protein translocates to the nucleus, where it stimulates cell proliferation. When T3 binds to TRβ1, the genomic consequences are normal thyroid hormone‐dependent biological activities, which also shows antiproliferative effect in cancer cells. However, the antiproliferative effect of TRβ1 is reduced by overexpression of D3 induced by TRα‐enhanced β‐catenin‐dependent mechanisms. In a mechanism that begins at the cell surface, T4 and, less avidly, T3 bind to integrin αvβ3 and activate ERK1/2 phosphorylation, and nongenomically stimulate cancer cell proliferation. When T3 binds to integrin αvβ3, it activates not only ERK1/2 by phosphorylation, but also activates Akt by triggering PI3K phosphorylation. Thus, Akt enhances HIF‐1α expression and then stimulates cancer cell metastasis. The opened‐boxes represent the normal signal pathways, however, colored‐boxes represent signals involved in the progression of cancers.
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Hung‐Yun Lin, Yu‐Tan Chin, Yu‐Chen S. H. Yang, Hsuan‐Yu Lai, Jacqueline Whang‐Peng, Leroy F. Liu, Heng‐Yuan Tang, Paul J. Davis. Thyroid Hormone, Cancer, and Apoptosis. Compr Physiol 2016, 6: 1221-1237. doi: 10.1002/cphy.c150035