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β-Adrenergic receptors suppress Rap1B prenylation and promote the metastatic phenotype in breast cancer cells. Cancer Biol Ther 2015;16(9):1364-74

Date

07/26/2015

Pubmed ID

26209110

Pubmed Central ID

PMC4622671

DOI

10.1080/15384047.2015.1070988

Scopus ID

2-s2.0-84941806664 (requires institutional sign-in at Scopus site)   43 Citations

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.

Author List

Wilson JM, Lorimer E, Tyburski MD, Williams CL

Author

Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adrenergic beta-2 Receptor Agonists
Adrenergic 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