Small molecule hormone or hormone-like ligands of integrin alphaVbeta3: implications for cancer cell behavior.

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Davis PJ, Mousa SA, Cody V, Tang HY, Lin HY

Small molecule hormone or hormone-like ligands of integrin alphaVbeta3: implications for cancer cell behavior.

Horm Cancer. 2013 Dec;4(6):335-42. doi: 10.1007/s12672-013-0156-8. Epub 2013 Aug 14.

PubMed ID

23943159 [ View in PubMed

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Abstract

Integrins are heterodimeric structural components of the plasma membrane whose ligands include a large number of extracellular matrix (ECM) proteins. The ligands contain Arg-Gly-Asp (RGD) sequences that enable recognition of ECM proteins by as many as eight integrins, but other distinguishing features of the proteins permit the integrins to generate intracellular signals specific to the ECM molecules. Recently, integrin alphavbeta3 has been shown to have a panel of previously unappreciated small molecule receptor sites for thyroid hormone and hormone analogues, for dihydrotestosterone, and for resveratrol, a polyphenol that has certain estrogen-like features. These binding sites are close to the RGD recognition site of alphavbeta3. The thyroid hormone receptor site on the extracellular domain of alphavbeta3 contains two domains with discrete functions in terms of intracellular protein trafficking and gene expression. Occupancy of the receptor by a deaminated thyroid hormone analogue, tetraiodothyroacetic acid (tetrac), prevents cell responses to agonist thyroid hormones (L-thyroxine; 3, 5, 3'-triiodo-L-thyronine) and modulates expression of a number of cancer cell survival pathway genes in an up- or downregulation pattern coherent to induction of cell death. The small molecule thyroid hormone receptor on the integrin also regulates activity of five vascular growth factor receptors and/or their ligands, providing control of angiogenesis via specific pharmacologic regulation of this thyroid hormone receptor. The resveratrol receptor induces programmed cancer cell death via p53, even when the latter has undergone specific mutations. There is also evidence for the presence of several receptors on integrin alphavbeta3 for authentic steroids, including a dihydrotestosterone site that supports proliferation of breast cancer cells that lack nuclear androgen and estrogen receptors. The existence of these small molecule hormone receptors on an integrin with a remarkably complex functional profile defines novel pharmacologic options via individual small molecule receptor manipulation for control of cancer cell behavior. This refinement of up-down control at the level of discrete receptors is not a function of the use of alphavbeta3 antibody or RGD peptides that occlude regions of the integrin.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Resveratrol	Integrin alpha-5	Protein	Humans	Unknown	Not Available	Details
Resveratrol	Integrin beta-3	Protein	Humans	Unknown	Not Available	Details