Thyroid Hormone, Hormone Analogs, and Angiogenesis

Davis, Paul J.; Sudha, Thangirala; Lin, Hung Yun; Mousa, Shaker A.

doi:10.1002/cphy.c150011

Cited by 55 publications

(51 citation statements)

References 83 publications

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“…This should be particularly relevant to GBM because of its extensive vascularity. NDAT inhibits actions of vascular endothelial growth factor (VEGF) [22, 46], basic fibroblast growth factor (bFGF) [47], platelet-derived growth factor (PDGF) (S.A. Mousa, unpublished observations), and epidermal growth factor (EGF) [48]. Depending on the growth factor, these effects can involve gene transcription, growth factor release, or inhibitory crosstalk between the thyroid hormone-tetrac receptor on integrin αvβ3 and the vascular growth factor receptors clustered with the integrin on or in the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

“…The antitumor effectiveness of NDAT involves pro-apoptotic activity and disruption of transcription of genes essential to a number of cancer cell survival pathways. The anti-angiogenic activity of NDAT involves disordering by several mechanisms of actions of endogenous growth factors, such as vascular endothelial growth factor (VEGF) [22], basic fibroblast growth factor (bFGF; FGF2) [22] and platelet-derived growth factor (PDGF) (S.A. Mousa, unpublished observations). NDAT also downregulates expression of the epidermal growth factor receptor ( EGFR ) gene [23].…”

Section: Introductionmentioning

confidence: 99%

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Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

et al. 2017

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Thyroid hormone as L-thyroxine (T4) stimulates proliferation of glioma cells in vitro and medical induction of hypothyroidism slows clinical growth of glioblastoma multiforme (GBM). The proliferative action of T4 on glioma cells is initiated nongenomically at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that blocks T4 action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) that increases the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of human GBM xenografts in immunodeficient mice, NDAT administered daily for 10 days subcutaneously as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p < 0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p < 0.001), without intratumoral hemorrhage. Up to 80% of tumor cells were necrotic in various microscopic fields (p < 0.001 vs. control tumors), an effect attributable to devascularization. There was substantial evidence of apoptosis in other fields (p < 0.001 vs. control tumors). Induction of apoptosis in cancer cells is a well-described quality of NDAT. In summary, systemic NDAT has been shown to be effective by multiple mechanisms in treatment of GBM xenografts.Electronic supplementary materialThe online version of this article (doi:10.1007/s12672-017-0293-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

et al. 2017

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“…For ovarian cancer patients, a significant increase was found only for T 4 ( P = 0.050) [15]. Extensive in vitro studies reviewed elsewhere have suggested that T 4 may play a more important role than T 3 in stimulating cancer cell proliferation [26]. …”

Section: Discussionmentioning

confidence: 99%

“…The stimulatory effect of thyroid hormone on cancer cell proliferation is largely expressed via a cell surface receptor for the hormone on the extracellular domain of integrin αvβ3 [26], rather than via nuclear thyroid hormone receptors (see below). We showed in the current studies that thyroid hormones stimulated proliferation of ovarian cancer cells with high levels of integrin αvβ3 through phosphorylation of ERK1/2 (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells

et al. 2016

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Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin αvβ3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T4) at a physiologic total hormone concentration (10−7 M) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3′-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Thyroid hormone (T4 and T3) treatment of human ovarian cancer cells resulted in enhanced activation of the Ras/MAPK(ERK1/2) signal transduction pathway. An MEK inhibitor (PD98059) blocked hormone-induced cell proliferation but not ER phosphorylation. Knock-down of either integrin αv or β3 by RNAi blocked thyroid hormone-induced phosphorylation of ERK1/2. We also found that thyroid hormone causes elevated phosphorylation and nuclear enrichment of estrogen receptor α (ERα). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin αv and phosphorylation of ERα. The specific ERα antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERα phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin αv and phosphorylated ERα was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERα and integrin αv are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin αv monomer to ERα promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin αv and ERα, mimicking functions of E2.

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“…In addition to TRβ1 and TRα, another binding site of thyroid hormone is the cell surface integrin α v β 3 . Physiologic concentrations of thyroid hormones ( l ‐thyroxine (T 4 ) and 3,5,3‐triiodo‐ l ‐thyronine (T 3) ) bind to an integrin α v β 3 receptor on the plasma membrane, and, in vitro , stimulate the growth of various tumor cell lines, including glioma cells, medullary thyroid and papillary thyroid cancer cells, lung cancer cells, breast cancer cells, colorectal cancer cells, pancreatic cancer carcinoma, renal cell cancer cells, and ovarian cancer cells . The growth of tumor cells promoted by thyroid hormone is dependent on activated ERK1/2, and an inhibitor of ERK1/2, PD 98059, inhibits the proliferative activity of the hormone.…”

Section: Steroid Hormonesmentioning

confidence: 99%

Mechanisms of action of nonpeptide hormones on resveratrol‐induced antiproliferation of cancer cells

Lin

Hsieh

Cheng

et al. 2017

Annals of the New York Academy of Sciences

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Nonpeptide hormones, such as thyroid hormone, dihydrotestosterone, and estrogen, have been shown to stimulate cancer proliferation via different mechanisms. Aside from their cytosolic or membrane-bound receptors, there are receptors on integrin α β for nonpeptide hormones. Interaction between hormones and integrin α β can induce signal transduction and eventually stimulate cancer cell proliferation. Resveratrol induces inducible COX-2-dependent antiproliferation via integrin α β . Resveratrol and hormone-induced signals are both transduced by activated extracellular-regulated kinases 1 and 2 (ERK1/2); however, hormones promote cell proliferation, while resveratrol induces antiproliferation in cancer cells. Hormones inhibit resveratrol-stimulated phosphorylation of p53 on Ser15, resveratrol-induced nuclear COX-2 accumulation, and formation of p53-COX-2 nuclear complexes. Subsequently, hormones impair resveratrol-induced COX-2-/p53-dependent gene expression. The inhibitory effects of hormones on resveratrol action can be blocked by different antagonists of specific nonpeptide hormone receptors but not integrin α β blockers. Results suggest that nonpeptide hormones inhibit resveratrol-induced antiproliferation in cancer cells downstream of the interaction between ligand and receptor and ERK1/2 activation to interfere with nuclear COX-2 accumulation. Thus, the surface receptor sites for resveratrol and nonpeptide hormones are distinct and can induce discrete ERK1/2-dependent downstream antiproliferation biological activities. It also indicates the complex pathways by which antiproliferation is induced by resveratrol in various physiological hormonal environments. .

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Thyroid Hormone, Hormone Analogs, and Angiogenesis

Cited by 55 publications

References 83 publications

Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells

Mechanisms of action of nonpeptide hormones on resveratrol‐induced antiproliferation of cancer cells

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