Membrane Receptor for Thyroid Hormone: Physiologic and Pharmacologic Implications

Plasma membrane integrin alpha nu beta 3 is a cell surface receptor for thyroid hormone at which nongenomic actions are initiated. L-thyroxine (T-4) and 3,3',5-triiodo-L-thyronine (T-3) promote ang-iogenesis and tumor cell proliferation via the receptor. Tetraiodothyroacetic acid (tetrac), a deaminated T-4 derivative, blocks the nongenomic proliferative and proangiogenic actions of T-4 and T-3. Acting at the integrin independently of T-4 and T-3, tetrac and a novel nanoparticulate formulation of tetrac that acts exclusively at the cell surface have oncologically desirable antiproliferative actions on multiple tumor cell survival pathway genes. These agents also block the angiogenic activity of vascular growth factors. Volume and vascular support ofxenografts of human pancreatic, kidney, lung, and breast cancers are downregulated by tetrac formulations. The integrin alpha nu beta 3 receptor site for thyroid hormone selectively regulates signal transduction pathways and distinguishes between unmodified tetrac and the nanoparticulate formulation. The receptor also mediates nongenomic thyroid hormone effects on plasma membrane ion transporters and on intracellular protein trafficking.