Cancer cell gene expression modulated from plasma membrane integrin αvβ3 by thyroid hormone and nanoparticulate tetrac

Integrin alpha v beta 3 is generously expressed by cancer cells and rapidly dividing endothelial cells. The principal ligands of the integrin are extracellular matrix proteins, but we have described a cell surface small molecule receptor on alpha v beta 3 that specifically binds thyroid hormone and thyroid hormone analogs. From this receptor, thyroid hormone (L-thyroxine, 1(4); 3,5,3'-triiodo-L-thyronine, T-3) and tetraiodothyroacetic acid (tetrac) regulate expression of specific genes by a mechanism that is initiated non-genomically. At the integrin, T-4 and 13 at physiological concentrations are pro-angiogenic by multiple mechanisms that include gene expression, and T-4 supports tumor cell proliferation. Tetrac blocks the transcriptional activities directed by T-4 and T-3 at alpha v beta 3, but, independently of T-4 and T-3, tetrac modulates transcription of cancer cell genes that are important to cell survival pathways, control of the cell cycle, angiogenesis, apoptosis, cell export of chemotherapeutic agents, and repair of double-strand DNA breaks. We have covalently bound tetrac to a 200 nm biodegradable nanoparticle that prohibits cell entry of tetrac and limits its action to the hormone receptor on the extracellular domain of plasma membrane alpha v beta 3. This reformulation has greater potency than unmodified tetrac at the integrin and affects a broader range of cancer relevant genes. In addition to these actions on intra-cellular kinase-mediated regulation of gene expression, hormone analogs at alpha v beta 3 have additional effects on intra-cellular protein trafficking (cytosol compartment to nucleus), nucleoprotein phosphorylation, and generation of nuclear coactivator complexes that are relevant to traditional genomic actions of T-3. Thus, previously unrecognized cell surface-initiated actions of thyroid hormone and tetrac formulations at alpha v beta 3 offer opportunities to regulate angiogenesis and multiple aspects of cancer cell behavior.