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

Abstract

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.

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

“…This transcription regulation is in concert with clustering of the dimeric αvβ3 protein on the cell surface, following thyroid hormones treatment. Similar clustering was shown by our group in myeloma, 28 but was also demonstrated for other immobilized or soluble ligands. [55][56][57][58] Pharmacologic inhibitors of the integrin blocked αv and β3 mRNA induction by T4.…”

“…The concentrations selected for T3 (1 nM) and T4 (100 nM) are slightly supraphysiological and physiological, respectively, as previously reported by our group in other experimental cancer models. [28][29][30] By using fluorescently dye-tagged T3 and T4, the membrane binding of the two hormones to OVCAR-3 cells (Figure 1b binding was scarcely detectable. Furthermore, an overnight incubation of OVCAR-3 cells with T3 or T4, induced clustering and abundance of the integrin on the cell surface by 2.5-fold and fourfold (quantified using NIH ImageJ software), respectively ( Figure 1c).…”

THRB (Thyroid Hormone Receptor, Beta)

“…However, these confusing data could result from activation of different and cell-specific mechanisms involved in genomic and nongenomic actions of T4/T3. TH has been shown to be a ERK1/2-dependent growth factor for Human Myeloma Cells acting via αvβ3 Integrin (Cohen et al, 2011). Several studies have demonstrated as well that T3 promotes growth and proliferation of cancer cells through TRβ1/Oct-1-mediated cyclin D1 activation that was confirmed in papillary thyroid carcinoma cell lines (Perri et al, 2013).…”

“…Tumor suppressor function of TRβ has been demonstrated in a mouse model of metastatic follicular thyroid carcinoma as well . According to the findings mentioned above, it could be hypothesized that TH may act as a growth, proangiogenic, pro-proliferative and anti-apoptotic factor when initiated at the nongenomic level (Cohen et al 2011;Davis, 2009), whereas in nucleus, TRβ1 could serve as a suppressor itself or mediating some genomic actions of T3 on specific genes involved in retardation of tumor growth and progression. (Martínez-Iglesias et al, 2009b;Kim at al., 2013).…”

Effect of non-genomic actions of thyroid hormones on the anaesthetic effect of propofol

“…Furthermore, the non-classical nuclear TR-mediated action of TH has been verified in human fibroblasts, human glioma, cardiomyocytes and osteoblasts. The GABAergic system is also an important target for the non-genomic action of THs (20)(21)(22)(23)(24)(25)(26).…”