Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells (original) (raw)
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PloS one, 2011
A cell surface receptor for thyroid hormone that activates extracellular regulated kinase (ERK) 1/2 has been identified on integrin αvβ3. We have examined the actions of thyroid hormone initiated at the integrin on human NCI-H522 non-small cell lung carcinoma and NCI-H510A small cell lung cancer cells. At a physiologic total hormone concentration (10(-7) M), T(4) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T(3)) at a supraphysiologic concentration. Neutralizing antibody to integrin αvβ3 and an integrin-binding Arg-Gly-Asp (RGD) peptide blocked thyroid hormone-induced PCNA expression. Tetraiodothyroacetic acid (tetrac) lacks thyroid hormone function but inhibits binding of T(4) and T(3) to the integrin receptor; tetrac eliminated thyroid hormone-induced lung cancer cell proliferation and ERK1/2 activation. In these estrogen receptor-α (ERα)-positive lung cancer cells, thyroid hormone (T(4)&g...
Cell Proliferation, 2007
Objectives : Although thyroid cancer occurs much more frequently in females, the role of sex hormones in thyroid carcinogenesis is unknown. In this study, it has been investigated how 17 β-oestradiol (E2) influenced proliferation and growth of thyroid cancer cells. Materials and Methods : Cell proliferation and its related molecules were examined in thyroid papillary carcinoma cells (KAT5), follicular thyroid carcinoma cells (FRO) and anaplastic carcinoma cells (ARO). Levels of oestrogen receptor (ER) α and β were regulated by their agonists (PPT and DPN), antagonists and siRNA. Results : E2 promoted cell proliferation. Such an effect was positively related to ER α but negatively to ER β ; PPT enhanced cell proliferation while DPN inhibited it. PPT increased Bcl-2 expression while DPN decreased it. DPN also elevated Bax expression. PPT elevated the level of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), suggesting a positive role of ERK1/2 in E2-induced cell proliferation. Knockdown of ER α significantly attenuated E2-mediated Bcl-2 and pERK1/2 expression. In contrast, knockdown of ER β markedly enhanced them. Conclusions : Oestrogen stimulates proliferation of thyroid cancer cells, associated with increase in Bcl-2 and decrease in Bax levels in an ERK1/2-related pathway. Imbalance between ER α and ER β may contribute to thyroid carcinogenesis.
International Journal of Oncology, 2010
Premenopausal women are at highest risk for papillary and follicular thyroid carcinoma, implicating a role for estrogens in thyroid cancer. The expression of estrogen receptors • and ß (ER), the effects of estradiol (E 2), selective estrogen receptor modulators (SERMs) 4-hydroxytamoxifen and raloxifene, and ER subtype selective agonists were examined in NPA87 and KAT5 papillary and WRO follicular thyroid carcinoma cell lines. All three thyroid cancer cell lines expressed full-length ER• and ERß proteins with cytoplasmic localization that was unaffected by E 2. ICI 182,780 (Fulvestrant, an ER antagonist), and inhibitors of non-genomic E 2-activated MAPK and PI3K signaling blocked E 2-induced cell proliferation. SERMs acted in a cell line-specific manner. No E 2-induced estrogen response element (ERE)-driven reporter activity was observed in transiently transfected thyroid cancer cells. However, E 2 increased transcription of established endogenous E 2-target genes, i.e., cathepsin D in WRO and cyclin D1 in both KAT5 and WRO cells in an ER-dependent manner as validated by inhibitor and siRNA experiments. In contrast, E 2 did not increase progesterone receptor expression in the thyroid cancer cell lines. E 2 stimulated phosphorylation of ERK1/2 in KAT5 and WRO cells and siER• or siERß inhibited E 2-induced ERK phosphorylation. Expression of the putative membrane estrogen receptor GPR30 was detected in WRO, but not NPA87 or KAT5 cells. GPR30 expression was lower in WRO than MCF-7 human breast cancer cells. Overall, these findings suggest E 2-mediated thyroid cancer cell proliferation involves ER• and ERß transcriptional and non-genomic signaling events.
International Journal of Molecular Sciences, 2019
Several physiological processes, including cellular growth, embryonic development, differentiation, metabolism and proliferation, are modulated by genomic and nongenomic actions of thyroid hormones (TH). Several intracellular and extracellular candidate proteins are regulated by THs. 3,3,5-Triiodo-L-thyronine (T3) can interact with nuclear thyroid hormone receptors (TR) to modulate transcriptional activities via thyroid hormone response elements (TRE) in the regulatory regions of target genes or bind receptor molecules showing no structural homology to TRs, such as the cell surface receptor site on integrin αvβ3. Additionally, L-thyroxine (T4) binding to integrin αvβ3 is reported to induce gene expression through initiating non-genomic actions, further influencing angiogenesis and cell proliferation. Notably, thyroid hormones not only regulate the physiological processes of normal cells but also stimulate cancer cell proliferation via dysregulation of molecular and signaling pathway...
Endocrinology, 2005
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 sugge...
Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms
Journal of Clinical …, 2001
Thyroid tumors are about 3 times more frequent in females than in males. Epidemiological studies suggest that the use of estrogens may contribute to the pathogenesis of thyroid tumors. In a very recent study a direct growth stimulatory effect of 17-estradiol was demonstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors ␣ and  in thyroid cells derived from human goiter nodules and in human thyroid carcinoma cell line HTC-TSHr was demonstrated. There was no difference between the expression levels of estrogen receptor ␣ in males and females, but there was a significant increase in expression levels in response to 17-estradiol. Stimulation of benign and malignant thyroid cells with 17-estradiol resulted in an increased proliferation rate and an enhanced expression of cyclin D1 protein, which plays a key role in the regulation of G 1 /S transition in the cell cycle. In malignant tumor cells maximal cyclin D1 expression was observed after 3 h, whereas in benign cells the effect of 17-estradiol was delayed. ICI 182780, a pure estrogen antagonist, prevented the effects of 17-estradiol. In addition, 17estradiol was found to modulate activation of mitogen-activated protein (MAP) kinase, whose activity is mainly regulated by growth factors in thyroid carcinoma cells. In response to 17-estradiol, both MAP kinase isozymes, extracellular signal-regulated protein kinases 1 and 2, were strongly phosphorylated in benign and malignant thyroid cells. Treatment of the cells with 17-estradiol and MAP kinase kinase 1 inhibitor, PD 098059, prevented the accumulation of cyclin D1 and estrogen-mediated mitogenesis. Our data indicate that 17estradiol is a potent mitogen for benign and malignant thyroid tumor cells and that it exerts a growth-promoting effect not only by binding to nuclear estrogen receptors, but also by activation of the MAP kinase pathway.
Estrogen Promotes Growth of Human Thyroid Tumor Cells by Different Molecular Mechanisms 1
The Journal of Clinical Endocrinology & Metabolism, 2001
Thyroid tumors are about 3 times more frequent in females than in males. Epidemiological studies suggest that the use of estrogens may contribute to the pathogenesis of thyroid tumors. In a very recent study a direct growth stimulatory effect of 17-estradiol was demonstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors ␣ and  in thyroid cells derived from human goiter nodules and in human thyroid carcinoma cell line HTC-TSHr was demonstrated. There was no difference between the expression levels of estrogen receptor ␣ in males and females, but there was a significant increase in expression levels in response to 17-estradiol. Stimulation of benign and malignant thyroid cells with 17-estradiol resulted in an increased proliferation rate and an enhanced expression of cyclin D1 protein, which plays a key role in the regulation of G 1 /S transition in the cell cycle. In malignant tumor cells maximal cyclin D1 expression was observed after 3 h, whereas in benign cells the effect of 17-estradiol was delayed. ICI 182780, a pure estrogen antagonist, prevented the effects of 17-estradiol. In addition, 17estradiol was found to modulate activation of mitogen-activated protein (MAP) kinase, whose activity is mainly regulated by growth factors in thyroid carcinoma cells. In response to 17-estradiol, both MAP kinase isozymes, extracellular signal-regulated protein kinases 1 and 2, were strongly phosphorylated in benign and malignant thyroid cells. Treatment of the cells with 17-estradiol and MAP kinase kinase 1 inhibitor, PD 098059, prevented the accumulation of cyclin D1 and estrogen-mediated mitogenesis. Our data indicate that 17estradiol is a potent mitogen for benign and malignant thyroid tumor cells and that it exerts a growth-promoting effect not only by binding to nuclear estrogen receptors, but also by activation of the MAP kinase pathway.
Cell Biochemistry and Function, 2013
The effects of 3,5,3′‐triiodo‐l‐thyronine (T3) and l‐thyroxine (T4) on the integrin αvβ3 receptor of thyroid hormones (TH) were investigated in pheochromocytoma PC‐12 cells. Differentiation was induced by treatment of PC‐12 cells with fisetin and the levels of phosphorylated extracellular signal‐regulated kinase (ERK) and Akt in cytoplasm, as well as the content of FoxO6 transcription factor in nuclei was analysed in undifferentiated and differentiated conditions. We have found that in undifferentiated PC‐12 cells, tetraiodothyroacetic acid (TETRAC), a known inhibitor of binding of T4 and T3 to plasma membrane integrin αvβ3 receptor inhibits T4‐dependent phosphorylation of ERK, whereas in differentiated PC‐12 cells, TETRAC abolishes the effect of T3. In undifferentiated PC‐12 cells, both TH increase the level of p‐Akt, and this enhancement is not sensitive to TETRAC. In differentiated PC‐12 cells, both TH increase the level of p‐Akt; however, only T3‐dependent activation of Akt is s...
Thyroid Hormone Controls Breast Cancer Cell Movement via Integrin αV/β3/SRC/FAK/PI3-Kinases
Hormones & cancer, 2017
Thyroid hormones (TH) play a fundamental role in diverse processes, including cellular movement. Cell migration requires the integration of events that induce changes in cell structure towards the direction of migration. These actions are driven by actin remodeling and stabilized by the development of adhesion sites to extracellular matrix via transmembrane receptors linked to the actin cytoskeleton. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that promotes cell migration and invasion through the control of focal adhesion turnover. In this work, we demonstrate that the thyroid hormone triiodothyronine (T3) regulates actin remodeling and cell movement in breast cancer T-47D cells through the recruitment of FAK. T3 controls FAK phosphorylation and translocation at sites where focal adhesion complexes are assembled. This process is triggered via rapid signaling to integrin αV/β3, Src, phosphatidylinositol 3-OH kinase (PI3K), and FAK. In addition, we established a cell...