Integrin αvβ3 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 αvβ3 that specifically binds
thyroid hormone and
thyroid hormone analogs. From this receptor,
thyroid hormone (
l-thyroxine, T4; 3,5,3'-triiodo-l-
thyronine, T3) and
tetraiodothyroacetic acid (
tetrac) regulate expression of specific genes by a mechanism that is initiated non-genomically. At the
integrin, T4 and T3 at physiological concentrations are pro-angiogenic by multiple mechanisms that include gene expression, and T4 supports
tumor cell proliferation.
Tetrac blocks the transcriptional activities directed by T4 and T3 at αvβ3, but, independently of T4 and T3,
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 αvβ3. 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 αvβ3 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 T3. Thus, previously unrecognized cell surface-initiated actions of
thyroid hormone and
tetrac formulations at αvβ3 offer opportunities to regulate angiogenesis and multiple aspects of
cancer cell behavior.