Translational implications of nongenomic actions of thyroid hormone initiated at its integrin receptor

2009 ◽  
Vol 297 (6) ◽  
pp. E1238-E1246 ◽  
Author(s):  
Paul J. Davis ◽  
Faith B. Davis ◽  
Hung-Yun Lin ◽  
Shaker A. Mousa ◽  
Min Zhou ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cell Surface ◽  
Tumor Cell ◽  
Cell Biology ◽  
Thyroid Hormone Receptor ◽  
Integrin Αvβ3 ◽  
Integrin Receptor ◽  
Cell Functions ◽  
Mediated Effects ◽  
Hormone Analogs

A thyroid hormone receptor on integrin αvβ3 that mediates cell surface-initiated nongenomic actions of thyroid hormone on tumor cell proliferation and on angiogenesis has been described. Transduction of the hormone signal into these recently recognized proliferative effects is by extracellular-regulated kinases 1/2 (ERK1/2). Other nongenomic actions of the hormone may be transduced by phosphatidylinositol 3-kinase (PI3K) and are initiated in cytoplasm or at the cell surface. PI3K-mediated effects are important to angiogenesis or other recently appreciated cell functions but apparently not to tumor cell division. For those actions of thyroid hormone [l-thyroxine (T4) and 3,3′-5-triiodo-l-thyronine (T3)] that begin at the integrin receptor, tetraiodothyroacetic acid (tetrac) is an inhibitor of and probe for the participation of the receptor in downstream intracellular events. In addition, tetrac has actions initiated at the integrin receptor that are unrelated to inhibition of the effects of T4 and T3 but do involve gene transcription in tumor cells. Discussed here are the implications of translating these nongenomic mechanisms of thyroid hormone analogs into clinical cancer cell biology, tumor-related angiogenesis, and modulation of angiogenesis that is not related to cancer.

scholarly journals Actions of Thyroid Hormones on Thyroid Cancers

2021 ◽  
Vol 12 ◽  
Author(s):  
Shaker A. Mousa ◽  
Aleck Hercbergs ◽  
Hung-Yun Lin ◽  
Kelly A. Keating ◽  
Paul J. Davis
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Differentiated Thyroid Cancer ◽  
Thyroid Hormone Receptor ◽  
Integrin Αvβ3 ◽  
Physiological Concentration ◽  
Thyroid Cancer Cells

L-Thyroxine (T4) is the principal ligand of the thyroid hormone analogue receptor on the extracellular domain of integrin αvβ3. The integrin is overexpressed and activated in cancer cells, rapidly dividing endothelial cells, and platelets. The biologic result is that T4 at physiological concentration and without conversion to 3,3’,5-triiodo-L-thyronine (T3) may stimulate cancer cell proliferation and cancer-relevant angiogenesis and platelet coagulation. Pro-thrombotic activity of T4 on platelets is postulated to support cancer-linked blood clotting and to contribute to tumor cell metastasis. We examine some of these findings as they may relate to cancers of the thyroid. Differentiated thyroid cancer cells respond to physiological levels of T4 with increased proliferation. Thus, the possibility exists that in patients with differentiated thyroid carcinomas in whom T4 administration and consequent endogenous thyrotropin suppression have failed to arrest the disease, T4 treatment may be stimulating tumor cell proliferation. In vitro studies have shown that tetraiodothyroacetic acid (tetrac), a derivative of T4, acts via the integrin to block T4 support of thyroid cancer and other solid tumor cells. Actions of T4 and tetrac or chemically modified tetrac modulate gene expression in thyroid cancer cells. T4 induces radioresistance via induction of a conformational change in the integrin in various cancer cells, although not yet established in thyroid cancer cells. The thyroid hormone receptor on integrin αvβ3 mediates a number of actions of T4 on differentiated thyroid cancer cells that support the biology of the cancer. Additional studies are required to determine whether T4 acts on thyroid cancer cells.

scholarly journals In Vivo Activity of the Thyroid Hormone Receptor β- and α-Selective Agonists GC-24 and CO23 on Rat Liver, Heart, and Brain

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1136-1142 ◽  
Author(s):  
Carmen Grijota-Martínez ◽  
Eric Samarut ◽  
Thomas S. Scanlan ◽  
Beatriz Morte ◽  
Juan Bernal
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Genetic Modifications ◽  
Hormone Analogs ◽  
Thyroid Hormone Receptor Β

Thyroid hormone analogs with selective actions through specific thyroid hormone receptor (TR) subtypes are of great interest. They might offer the possibility of mimicking physiological actions of thyroid hormone with receptor subtype or tissue specificity with therapeutic aims. They are also pharmacological tools to dissect biochemical pathways mediated by specific receptor subtypes, in a complementary way to mouse genetic modifications. In this work, we studied the in vivo activity in developing rats of two thyroid hormone agonists, the TRβ-selective GC-24 and the TRα-selective CO23. Our principal goal was to check whether these compounds were active in the rat brain. Analog activity was assessed by measuring the expression of thyroid hormone target genes in liver, heart, and brain, after administration to hypothyroid rats. GC-24 was very selective for TRβ and lacked activity on the brain. On the other hand, CO23 was active in liver, heart, and brain on genes regulated by either TRα or TRβ. This compound, previously shown to be TRα-selective in tadpoles, displayed no selectivity in the rat in vivo.

scholarly journals Lack of Mutations in the Thyroid Hormone Receptor (TR) α and β Genes but Frequent Hypermethylation of the TRβ Gene in Differentiated Thyroid Tumors

2007 ◽  
Vol 92 (12) ◽  
pp. 4766-4770 ◽  
Author(s):  
Biju Joseph ◽  
Meiju Ji ◽  
Dingxie Liu ◽  
Peng Hou ◽  
Mingzhao Xing
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Cell ◽  
Gene Mutation ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Thyroid Tumor ◽  
Thyroid Tumors ◽  
Tumor Cell Lines ◽  
Thyroid Adenomas

Abstract Context: It remains inconclusive whether mutations in thyroid hormone receptor (TR) genes naturally occur in thyroid cancer and whether these genes could be suppressors of this cancer. Objectives: Our objectives were to examine further mutations of TRα and TRβ genes in thyroid cancer and also to examine their methylation as an epigenetic silencing mechanism in thyroid cancer. Experimental Design: Instead of using a cDNA sequencing approach used in previous studies, we used genomic DNA to sequence directly the coding regions of the TRα and TRβ genes to search mutations in various differentiated thyroid tumors and used methylation-specific PCR to analyze promoter methylation of these genes. Allelic zygosity status at TRβ was also analyzed. Results: We found no TRα gene mutation in 17 papillary thyroid cancers (PTCs) and 11 follicular thyroid cancers (FTCs), and no TRβ gene mutation in 16 PTCs and 12 FTCs. We also found no methylation of the TRα gene in 33 PTCs, 31 FTCs, 20 follicular thyroid adenomas (FTAs), and 10 thyroid tumor cell lines. In contrast, we found hypermethylation of the TRβ gene in 10 of 29 (34%) PTCs, 22 of 27 (81%) FTCs, five of 20 (25%) follicular thyroid adenomas, and three of 10 (30%) thyroid tumor cell lines, with the highest prevalence in FTC. We additionally examined loss of heterozygosity at TRβ and found it in three of nine (33%) PTCs and three of nine (33%) FTCs. Conclusions: Mutation is not common in TR genes, whereas hypermethylation of the TRβ gene as an alternative gene silencing mechanism is highly prevalent in thyroid cancer, particularly FTC, consistent with a possible tumor suppressor role of this gene for FTC.

Cytoplasm-To-Nucleus Shuttling Of Thyroid Hormone Receptor-β1 (Trβ1) Is Directed From A Plasma Membrane Integrin Receptor By Thyroid Hormone

2009 ◽  
Vol 34 (1-2) ◽  
pp. 31-42 ◽  
Author(s):  
H. James Cao ◽  
Hung-Yun Lin ◽  
Mary K. Luidens ◽  
Faith B. Davis ◽  
Paul J. Davis
Keyword(s):  
Plasma Membrane ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Integrin Receptor

scholarly journals Chemically-Modified Tetraiodothyroacetic Acid (Tetrac) Induces Cancer Cell Apoptosis and Facilitates Clearance of Apoptotic Debris (Efferocytosis)

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1012-A1013
Author(s):  
Kavitha Godugu ◽  
Hung-yun Lin ◽  
Shaker A Mousa ◽  
Paul J Davis
Keyword(s):  
Thyroid Hormone ◽  
Drug Treatment ◽  
Tumor Cell ◽  
Molecular Mechanisms ◽  
Integrin Αvβ3 ◽  
Hormone Analogue ◽  
Human Glioblastoma ◽  
Chemically Modified ◽  
End Of Treatment ◽  
Apoptotic Change

Abstract Tetraiodothyroaetic acid (tetrac) is a derivative of L-thyroxine with anticancer properties. By multiple molecular mechanisms, tetrac and chemically-modified tetrac induce apoptosis in a variety of human cancer cells in vitro and in xenografts. The anticancer activities of tetrac are initiated at the thyroid hormone analogue receptor on the extracellular domain of plasma membrane integrin αvβ3 (PJ Davis et al., Physiol Rev 101:319-352, 2021). Induction of apoptosis in glioblastoma xenograft with chemically modified tetrac (P-bi-TAT) has yielded 90% in volume of grafts that continues after discontinuation of tetrac. In the present study, we show that human glioblastoma xenograft shrinkage in response to P-bi-TAT is associated with local appearance of phagocytic monocytes and clearance of apoptotic debris (efferocytosis). Primary culture xenograft of glioblastoma cells (GBM 052814, kindly provided by the University of Pittsburgh Medical Center, Department of Neurosurgery) and U87-luc (ATCC, Manassas, VA) xenografts were generated in 5-member groups of nude mice for each tumor cell type and for controls. Five days post-implantation, injection of animals was begun with PBS (control) or P-bi-TAT (10 mg/kg body weight). Injection was continued X21 days and animals were then maintained off-treatment for an additional 21 days. Tumors were harvested, formalin-fixed and slide-mounted, then analyzed by TUNEL assay for apoptosis and by anti-CD68 staining for monocytic macrophage content. Histologic analysis (H&E staining) was also carried out. TUNEL analysis and histopathology of both xenograft models revealed more than 90% apoptotic change with 21-days of P-bi-TAT treatment (P <0.001) and persistence of 40% apoptotic change 3 weeks post-discontinuation of drug (P<0.001 vs. end of treatment change). By H&E histology and CD68 analysis, monocytes accounted for more than 90% of the viable cells after 3 weeks’ drug treatment. Sixty percent of the end-of-treatment monocyte population persisted 3 weeks after discontinuation of P-bi-TAT (P <0.001). Histology revealed negligible cell debris after 3 weeks of drug treatment and at 3 weeks post-discontinuation of P-bi-TAT. Thus, the anticancer/pro-apoptotic action of tetrac-containing P-bi-TAT is associated with efferocytosis that contributes to the frank tumor shrinkage that results from P-bi-TAT treatment of human glioblastoma xenografts. This is the first documentation of efferocytosis regulated from the thyroid hormone analogue receptor on tumor cell integrin αvβ3.

Ontogenesis of thyroid hormone receptor in foetal lambs

1987 ◽  
Vol 116 (2) ◽  
pp. 205-210 ◽  
Author(s):  
Beatriz Ferreiro ◽  
Juan Bernal ◽  
Brian J. Potter
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Binding Capacity ◽  
Sedimentation Coefficient ◽  
Receptor Sites ◽  
Nuclear Extracts ◽  
Hormone Analogs ◽  
Neuroblast Proliferation ◽  
The Brain ◽  
Foetal Lamb

Abstract. Affinity and concentration of T3 receptor sites have been measured in nuclear extracts from the brain, lung, and liver of foetal lamb tissues at 50, 82 and 100 days of gestational age. Control experiments indicated that the concentration of sites was similar when nuclear extracts or purified nuclei were used, and that maximal binding capacity was obtained after 2 h of incubation at 22°C. The pattern of receptor binding affinity when different thyroid hormone analogs were used in competition assays with [125I]T3 was T3 > 3,5,3'-triiodothyroacetic acid (Triac) > T4 in the lung and brain. In the liver, Triac had the same affinity as T3. The sedimentation coefficient of the receptor was 3.6 S in lung. There were minor changes of receptor affinity in the brain, but not in the lung or liver, during development with the highest value at 82 days. Receptor concentration increased twice from 50 to 82 days. Since in the brain this is the period of neuroblast proliferation, the results suggest that thyroid hormone is required for proper foetal lamb development and, in particular, for neuroblast proliferation and/or differentiation.

scholarly journals Integrin αVβ3 Contains a Cell Surface Receptor Site for Thyroid Hormone that Is Linked to Activation of Mitogen-Activated Protein Kinase and Induction of Angiogenesis

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 2864-2871 ◽  
Author(s):  
Joel J. Bergh ◽  
Hung-Yun Lin ◽  
Lawrence Lansing ◽  
Seema N. Mohamed ◽  
Faith B. Davis ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Thyroid Hormone ◽  
Cell Surface ◽  
Matrix Protein ◽  
Integrin Αvβ3 ◽  
Recognition Site ◽  
Cell Surface Receptor ◽  
Extracellular Matrix Protein ◽  
Surface Receptor ◽  
A Cell

Abstract Integrin αVβ3 is a heterodimeric plasma membrane protein whose several extracellular matrix protein ligands contain an RGD recognition sequence. This study identifies integrin αVβ3 as a cell surface receptor for thyroid hormone [l-T4 (T4)] and as the initiation site for T4-induced activation of intracellular signaling cascades. Integrin αVβ3 dissociably binds radiolabeled T4 with high affinity, and this binding is displaced by tetraiodothyroacetic acid, αVβ3 antibodies, and an integrin RGD recognition site peptide. CV-1 cells lack nuclear thyroid hormone receptor, but express plasma membrane αVβ3; treatment of these cells with physiological concentrations of T4 activates the MAPK pathway, an effect inhibited by tetraiodothyroacetic acid, RGD peptide, and αVβ3 antibodies. Inhibitors of T4 binding to the integrin also block the MAPK-mediated proangiogenic action of T4. T4-induced phosphorylation of MAPK is inhibited by small interfering RNA knockdown of αV and β3. These findings suggest that T4 binds to αVβ3 near the RGD recognition site and show that hormone-binding to αVβ3 has physiological consequences.

scholarly journals New Interfaces of Thyroid Hormone Actions With Blood Coagulation and Thrombosis

2018 ◽  
Vol 24 (7) ◽  
pp. 1014-1019 ◽  
Author(s):  
Paul J. Davis ◽  
Shaker A. Mousa ◽  
Geraldine P. Schechter
Keyword(s):  
Thyroid Hormone ◽  
Clinical Evidence ◽  
Thyroid Hormone Receptor ◽  
Integrin Αvβ3 ◽  
Cell Interaction ◽  
Cytokines And Chemokines ◽  
Routine Measurement ◽  
Clinically Significant ◽  
Platelet Functions

Substantial clinical evidence indicates hyperthyroidism enhances coagulation and increases the risk of thrombosis. In vitro and clinical evidence implicate multiple mechanisms for this risk. Genomic actions of thyroid hormone as 3,5,3′-triiodo-L-thyronine (T3) via a nuclear thyroid hormone receptor have been implicated, but recent evidence shows that nongenomic mechanisms initiated at the receptor for L-thyroxine (T4) on platelet integrin αvβ3 are prothrombotic. The T4-initiated mechanisms involve platelet activation and, in addition, cellular production of cytokines and chemokines such as CX3CL1 with procoagulatory activities. These procoagulant actions of T4 are particulary of note because within cells T4 is not seen to be functional, but to be only a prohormone for T3. Finally, it is also possible that thyroid hormone stimulates platelet-endothelial cell interaction involved in local thrombus generation. In this brief review, we survey mechanisms by which thyroid hormone is involved in coagulation and platelet functions. It is suggested that the threshold should be lowered for considering the possibility that clinically significant clotting may complicate hyperthyroidism. The value of routine measurement of partial thromboplastin time or circulating D-dimer in patients with hyperthyroid or in patients treated with thyrotropin-suppressing dosage of T4 requires clinical testing.

Sign in / Sign up

Export Citation Format

Share Document