Cancer Cell Gene Expression Modulated from Plasma Membrane Integrin αvβ3 by Thyroid Hormone and Nanoparticulate Tetrac

摘要: 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 that specifically binds thyroid hormone analogues. From this receptor, (L-thyroxine, T4; 3,5,3’-triiodo-L-thyronine, T3) tetraiodothyroacetic acid (tetrac) regulate expression specific genes mechanism initiated nongenomically. At integrin, T4 T3 at physiological concentrations pro-angiogenic multiple mechanisms include gene expression, supports tumor proliferation. Tetrac blocks transcriptional activities directed αvβ3, but, independently T3, tetrac modulates transcription important to survival pathways, control cycle, angiogenesis, apoptosis, export chemotherapeutic agents repair double-strand DNA breaks. We covalently bound 200 nm biodegradable nanoparticle prohibits entry limits its action domain plasma membrane αvβ3. This reformulation has greater potency than unmodified affects broader range cancer-relevant genes. In addition these actions intracellular kinase-mediated regulation analogues additional effects protein-trafficking (cytosol compartment nucleus), nucleoprotein phosphorylation generation nuclear coactivator complexes relevant traditional genomic T3. Thus, previously unrecognized surface-initiated formulations offer opportunities angiogenesis aspects behavior.