Membrane receptor for thyroid hormone: physiologic and pharmacologic implications.
Plasma membrane integrin αvβ3 is a cell surface receptor for thyroid hormone at which nongenomic actions are initiated. L-thyroxine (T₄) and 3,3',5-triiodo-L-thyronine (T₃) promote angiogenesis and tumor cell proliferation via the receptor. Tetraiodothyroacetic acid (tetrac), a deaminated T₄ derivative, blocks the nongenomic proliferative and proangiogenic actions of T₄ and T₃. Acting at the integrin independently of T₄ and T₃, 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 of xenografts of human pancreatic, kidney, lung, and breast cancers are downregulated by tetrac formulations. The integrin αvβ3 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.
Davis
Paul J
PJ
Ordway Research Institute, Albany, New York 12208, USA. pdavis@ordwayresearch.org
Davis
Faith B
FB
Mousa
Shaker A
SA
Luidens
Mary K
MK
Lin
Hung-Yun
HY
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction; D013974:Thyroxine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D014284:Triiodothyronine / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D014284:Triiodothyronine; C011126:tetraiodothyroacetic acid; D013974:Thyroxine