Membrane Receptor for Thyroid Hormone: Physiologic and Pharmacologic Implications

Abstract

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.

Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression

“…These effects are initiated nongenomically, i.e., are independent of the classical nuclear receptor for thyroid hormone (TR) (Cheng et al, 2010), and may have downstream intracellular consequences that involve specific protein trafficking (Cao et al, 2009) and modulation of expression of specific genes involved in cancer cell survival pathways. Covalently bound to a biodegradable nanoparticle that is unable to access the interior of the cell, a thyroid hormone derivative, tetraiodothyroacetic acid (tetrac), acts exclusively at a receptor site on integrin v3 to block actions of L-thyroxine (T 4 ) and 3, 5, 3'-triiodo-L-thyronine (T 3 ) on new blood vessel formation and cancer cell division ; However, nanoparticulate tetrac (nanotetrac) and, to a lesser extent, unmodified tetrac have a panel of cancer-relevant actions in the absence of T 4 and T 3 Davis et al, 2011). These actions include modulation of tumor cell chemosensitivity (Rebbaa, A., et al, 2008), disordering of crosstalk between the integrin and nearby receptors for vascular endothelial growth factor (VEGF) Luidens et al, 2010) and epidermal growth factor (EGF) (Lin et al, 1999;Shih et al, 2004), and antagonism of components of the inflammatory process that may be important to cancer cell biology.…”

Emerging therapies for pancreatic ductal carcinoma

“…Integrin αvβ3 is a structural protein of the plasma membrane whose extracellular domain contains receptors for large molecule (extracellular matrix protein) [61] and small molecule (thyroid hormone) [62] ligands. The integrin is primarily expressed by tumor cells and dividing endothelial cells.…”

“…A thyroid hormone analogue, tetraiodothyroacetic acid (tetrac), acts at αvβ3 to generate intracellular signals that disorder expression of genes critical to cancer cell survival pathways, to angiogenesis, to cell division and repair of double-strand DNA breaks. [62][63][64] Inside the tumor cell, unmodified tetrac lacks these properties. [62] Covalently bound via a linker to a 120-150 nm nanoparticle, tetrac as Nano-diamino-tetrac (Nanotetrac) acts exclusively at the integrin [65] as an anticancer, anti-angiogenic agent.…”

“…[62][63][64] Inside the tumor cell, unmodified tetrac lacks these properties. [62] Covalently bound via a linker to a 120-150 nm nanoparticle, tetrac as Nano-diamino-tetrac (Nanotetrac) acts exclusively at the integrin [65] as an anticancer, anti-angiogenic agent. It has been shown to be effective against human pancreatic cancer cell xenografts [66] via induction of apoptosis and antiangiogenesis by multiple mechanisms.…”

“…It has been shown to be effective against human pancreatic cancer cell xenografts [66] via induction of apoptosis and antiangiogenesis by multiple mechanisms. This nanotechnologic design strategy has resulted in increased anticancer potency of Nano-diamino-tetrac vs. tetrac at the integrin by up to 10-fold [62] and to broaden the agent's anticancer transcriptional activity. For example, Nano-diamino-tetrac (but not unmodified tetrac) decreases expression of the EGFR gene and proto-oncogenic, pro-angiogenic miR-21 (SA Mousa, T Sudha: unpublished observations) and increases expression of pro-apoptotic BCL2L14.…”