Thyroid hormone stimulation of extracellular signal-regulated kinase and cell proliferation in human osteoblast-like cells is initiated at integrin αVβ3

Scarlett, AL; Parsons, Malcolm; Hanson, Philippa; Sidhu, KK; Milligan, TP; Burrin, JM

doi:10.1677/joe-07-0344

Cited by 47 publications

(24 citation statements)

References 25 publications

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“…Our findings are congruent with the recent demonstration that T 3 and, with greater potency, T 4 initiate cell proliferation in a number of tumor cell lines including breast cancer (31), hepatocarcinoma (32), somatotrophic tumor (33), thyroid cancer (28), sarcoma (34), and tumorassociated vascular cells via activation of a MAPK/ERK1/2-dependent pathway (16). This recently recognized role of the hormone is nongenomic in that it is initiated at a plasma Figure 5.…”

Section: Discussionsupporting

confidence: 92%

Thyroid Hormone Is a MAPK-Dependent Growth Factor for Human Myeloma Cells Acting via αvβ3 Integrin

Cohen

Ellis

Khoury

et al. 2011

Molecular Cancer Research

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Experimental and clinical observations suggest that thyroid hormone [L-thyroxine (T 4 ) and 3,5,30 -triiodo-Lthyronine (T 3 )] can support cancer cell proliferation. T 3 and T 4 promote both tumor cell division and angiogenesis by activating mitogen-activated protein kinase (MAPK) via binding to a hormone receptor on the avb3 integrin, overexpressed on many cancer cells. We have studied the responsiveness of several MM cell lines to T 3 and T 4 and characterized hormonal effects on cell survival, proliferation, and MAPK activation. Overnight T 3 (1-100 nmol/L) and T 4 (100 nmol/L) incubation enhanced, up to 50% (P < 0.002), MM cell viability (WST-1 assay) and increased cell proliferation by 30% to 60% (P < 0.01). Short exposure (10 minutes) to T 3 and T 4 increased MAPK activity by 2.5-to 3.5-fold (P < 0.03). Pharmacologic MAPK inhibition blocked the proliferative action of T 3 and T 4 . Antibodies to the integrin avb3 dimer and av and b3 monomers (but not b1) inhibited MAPK activation and subsequent cell proliferation in response to thyroid hormone, indicating dependence upon this integrin. Moreover, tetraiodothyroacetic acid (tetrac), a non-agonist T 4 analogue previously shown to selectively block T 3 /T 4 binding to avb3 receptor site, blocked induction of MAPK by the hormones in a dose-dependent manner. This demonstration of the role of thyroid hormones as growth factors for MM cells may offer novel therapeutic approaches. Mol Cancer Res; 9(10); 1385-94. Ó2011 AACR.

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Section: Discussionsupporting

confidence: 92%

Thyroid Hormone Is a MAPK-Dependent Growth Factor for Human Myeloma Cells Acting via αvβ3 Integrin

Cohen

Ellis

Khoury

et al. 2011

Molecular Cancer Research

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“…There are also data showing that in vitro thyroid hormones affect the energy metabolism in the bone remodelling process. T4 has been found to induce bone formation, differentiation, and mineralization in osteoblast- or osteoblast-like cells [27, 28]; more importantly, Gouveia et al revealed that T3 acted on the osteoblast-like cell mitochondrial gene ATPase 6 [29]. Although Kanatani et al discovered that T3 directly stimulated osteoclast differentiation [6] and Ma and Dai suggested that T3 stimulated osteoclast differentiation indirectly [30], only a few studies have investigated the effect of T4 on osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Energy Metabolism in the Bone is Associated with Histomorphometric Changes in Rats with Hyperthyroidism

Lai

et al. 2018

Cell Physiol Biochem

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Background/Aims: In this study we assessed histomorphometric changes induced by thyroxine (T4) in 3-month-old hyperthyroid male rats and examined whether the potential mechanism of these changes is related to bone changes. Methods: Rats were classified as either hyperthyroid following administration of 250 µg/kg/day freshly prepared T4 by gavage for 2 months or euthyroid following administration of vehicle alone (n = 8 per group). We measured bone mineral density (BMD), bone biomechanical properties, and bone histomorphometric changes. Levels of serum indicators were also measured, and three right femurs from the two groups were selected for proteomic investigation. Results: Compared with the control rats, hyperthyroid rats showed a reduction in the fifth lumbar vertebral BMD as well as in the entire femoral BMD (p = 0.033 and 0.026, respectively). Histomorphometric analysis of the proximal tibial metaphysis showed that the percentage of the trabecular area, trabecular number, and percentage of the cortical bone area in the hyperthyroid rats significantly decreased compared with those of the control rats. Conversely, bone formation rate (per unit of bone surface and bone volume), percentage of the osteoclast perimeter, trabecular separation, and endosteal mineral apposition rate in the hyperthyroid rats significantly increased compared with the control rats (all p < 0.05). Except for stiffness (p = 0.24), all bone biomechanical properties of the femur showed a significant decreasing trend in the hyperthyroid rats versus the control rats (all p < 0.05). Serum levels of osteocalcin, alkaline phosphatase, terminal telopeptides of type β collagen, and tartrate-resistant acid phosphatase were higher in the hyperthyroid rats than in the control rats (all p < 0.05). Using isobaric tags for relative and absolute quantification (iTRAQ), the expression levels of 1,310 proteins were found to be significantly different between the hyperthyroid and control rats (711 proteins were upregulated and 599 were downregulated in hyperthyroid rats). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses showed that most of the enzymes in the glycolysis–tricarboxylic acid (TCA) cycle–oxidative phosphorylation signalling pathway were upregulated in hyperthyroid rats, and seven differentially expressed proteins were selected to verify the iTRAQ results using western blotting. Conclusion: Energy metabolism via the glycolysis–TCA cycle–oxidative phosphorylation pathway is positively associated with T4-induced bone histomorphometric changes in rats.

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“…62 This trafficking event was also shown to be ERK-dependent. 62 Given that the activation of ERK has been closely correlated with the thyroid hormonal action in cancer cells, 17,18,26,[28][29][30][63][64][65][66][67][68][69] together with the central role of MAPK in ovarian cancer, 70 led us to explore this pathway in our experimental system. Results in ovarian cancer cells similarly indicate activation of ERK by the hormones.…”

Section: Discussionmentioning

confidence: 99%

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

et al. 2015

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Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvβ3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvβ3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvβ3) and A2780 (low αvβ3) cells promoted αv and β3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvβ3 antibodies, excluding T3-induced β3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of β3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvβ3-deficient HEK293 cells treated with αvβ3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the β3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical role for thyroid hormones as potent αvβ3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.

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Thyroid hormone stimulation of extracellular signal-regulated kinase and cell proliferation in human osteoblast-like cells is initiated at integrin αVβ3

Cited by 47 publications

References 25 publications

Thyroid Hormone Is a MAPK-Dependent Growth Factor for Human Myeloma Cells Acting via αvβ3 Integrin

Thyroid Hormone Is a MAPK-Dependent Growth Factor for Human Myeloma Cells Acting via αvβ3 Integrin

Energy Metabolism in the Bone is Associated with Histomorphometric Changes in Rats with Hyperthyroidism

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

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