β-Adrenergic receptors suppress Rap1B prenylation and promote the metastatic phenotype in breast cancer cells. Cancer Biol Ther 2015;16(9):1364-74
Date
07/26/2015Pubmed ID
26209110Pubmed Central ID
PMC4622671DOI
10.1080/15384047.2015.1070988Scopus ID
2-s2.0-84941806664 (requires institutional sign-in at Scopus site) 43 CitationsAbstract
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.
Author List
Wilson JM, Lorimer E, Tyburski MD, Williams CLAuthor
Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adrenergic beta-2 Receptor AgonistsAdrenergic beta-Antagonists
Aminopyridines
Breast Neoplasms
Cell Adhesion
Cell Line, Tumor
Cell Membrane
Cell Movement
Female
GTP-Binding Protein alpha Subunits, Gs
Humans
Isoproterenol
Neoplasm Metastasis
Phenotype
Phosphorylation
Propranolol
Protein Prenylation
Protein Transport
Receptors, Adrenergic, beta
Signal Transduction
rap GTP-Binding Proteins