title: β-Adrenergic receptors suppress Rap1B prenylation and promote the metastatic phenotype in breast cancer cells.
abstract: A greater understanding of the molecular basis of breast cancer metastasis will lead to identification of novel therapeutic targets and better treatments. Rap1B is a small GTPase that suppresses the metastasis of breast cancer cells by increasing cell-cell adhesion. In breast cancer, a decrease in Rap1B prenylation and subsequent loss of Rap1B at the plasma membrane decreases cell-cell adhesion and increases cell scattering, which promotes the metastatic phenotype. Protein kinase A (PKA) was recently found to phosphorylate Rap1B and inhibit its prenylation. PKA is activated by G protein-coupled receptors (GPCR) that stimulate Gαs. In this study, we investigated whether the general Gαs activator, cholera toxin, and agonists of the β-adrenergic receptor (βAR), which is a Gαs-coupled GPCR, promote Rap1B phosphorylation and inhibit its prenylation. We show here that cholera toxin and βAR activation phosphorylate Rap1B and inhibit its prenylation and membrane localization, reducing cell-cell adhesion and promoting cell scattering. Furthermore, we report that breast cancer cell migration is decreased by the FDA-approved β-blocker, propranolol. Pharmacological targeting of GPCRs, especially those such as the βAR that are regulated by FDA-approved drugs, to increase cell adhesion and decrease cell scattering could provide a promising therapeutic approach to reduce breast cancer metastasis.
authors.affiliation: a From the Department of Pharmacology and Toxicology ; Cancer Center and Cardiovascular Center; Medical College of Wisconsin ; Milwaukee , WI USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: a From the Department of Pharmacology and Toxicology ; Cancer Center and Cardiovascular Center; Medical College of Wisconsin ; Milwaukee , WI USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Lorimer
authors.affiliation: b Department of Political Science ; Tulane University ; New Orleans , LA USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Tyburski
authors.affiliation: a From the Department of Pharmacology and Toxicology ; Cancer Center and Cardiovascular Center; Medical College of Wisconsin ; Milwaukee , WI USA.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Williams
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D009362:Neoplasm Metastasis; D010641:Phenotype; D010766:Phosphorylation; D011433:Propranolol / Q000494:pharmacology; D017368:Protein Prenylation; D021381:Protein Transport; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction; D020668:rap GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D000631:Aminopyridines; C518875:BAY 60-6583; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; C116753:RAP1B protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D020668:rap GTP-Binding Proteins; D007545:Isoproterenol
keywords: G protein-coupled receptor; Ras-related protein 1 (Rap1); adenosine receptor; breast cancer; cholera toxin; protein isoprenylation; protein kinase A (PKA); β-adrenergic receptor