Abstract
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), T4 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. 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 T4 and T3 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 (T4>T3) caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T4-induced, but not T3-induced ERK1/2 activation, as well as ERα phosphorylation, proliferating-cell nuclear antigen (PCNA) expression and hormone-dependent thymidine uptake by tumor cells. Thus, in ERα-positive human lung cancer cells, the proliferative action of thyroid hormone initiated at the plasma membrane is at least in part mediated by ERα. In summary, thyroid hormone may be one of several endogenous factors capable of supporting proliferation of lung cancer cells. Activity as an inhibitor of lung cancer cell proliferation induced at the integrin receptor makes tetrac a novel anti-proliferative agent.
Highlights
Thyroid hormone has important roles in regulation of cellular metabolism and of cell proliferation and differentiation [1,2]
Because we have shown that thyroid hormones bind to a receptor on integrin avb3, we investigated whether integrin avb3 was expressed in NCI-H522 and NCI-H510A cells
Acting at the cell surface integrin avb3 receptor for thyroid hormone, T4 and T3 induced cell proliferation in the human lung cancer cell lines studied in the present report
Summary
Thyroid hormone has important roles in regulation of cellular metabolism and of cell proliferation and differentiation [1,2]. The hormone, usually as 3, 5, 39-triiodo-L-thyronine (T3), stimulates proliferation of a variety of nonmalignant cells, including hepatocytes [3,4], renal tubular epithelial cells and bone marrow cells [5] It may inhibit proliferation of certain cells, e.g., fetal cardiomyocytes [6]. In the case of estrogen receptor (ER)-positive breast cancer cells, we have described dependence of the proliferative effect of thyroid hormone on induction of mitogen-activated protein kinase-dependent serine phosphorylation of ERa that mimics the effect of estrogen [7]. This effect of thyroid hormone can be blocked by the estrogen receptor antagonist, ICI 182,780. There may be crosstalk between thyroid hormone and estrogen signaling pathways in certain cancer cells; these pathways originate nongenomically outside the nucleus and require ERK1/ ERK2, but culminate in specific intranuclear events
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
