Crosstalk between integrin αvβ3 and estrogen receptor-α is involved in thyroid hormone-induced proliferation in human lung carcinoma cells.

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), 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)>T(3)) caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T(4)-induced, but not T(3)-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.

• Authors: Ran Meng, Heng-Yuan Tang, Jennifer Westfall, David London, James H Cao, Shaker A Mousa, Mary Luidens, Aleck Hercbergs, Faith B Davis, Paul J Davis, Hung-Yun Lin
• Journal: PloS one (PLoS One) Vol. 6 Issue 11 Pg. e27547 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22132110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• Integrin alphaVbeta3
• Proliferating Cell Nuclear Antigen
• Thyroid Hormones
• Fulvestrant
• Estradiol
• Extracellular Signal-Regulated MAP Kinases
• tetraiodothyroacetic acid
• Thyroxine

Topics

• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Enzyme Activation (drug effects)
• Estradiol (analogs & derivatives, pharmacology)
• Estrogen Receptor alpha (metabolism)
• Extracellular Signal-Regulated MAP Kinases
• Fulvestrant
• Humans
• Integrin alphaVbeta3 (metabolism)
• Lung Neoplasms (enzymology, metabolism, pathology)
• Phosphorylation (drug effects)
• Proliferating Cell Nuclear Antigen (metabolism)
• Protein Transport (drug effects)
• Signal Transduction (drug effects)
• Thyroid Hormones (pharmacology)
• Thyroxine (analogs & derivatives, pharmacology)