A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway.

Abstract

A chemical biology approach identifies a beta 2 adrenergic receptor (beta2AR) agonist ARA-211 (Pirbuterol), which causes apoptosis and human tumor regression in animal models. beta2AR stimulation of cAMP formation and protein kinase A (PKA) activation leads to Raf-1 (but not B-Raf) kinase inactivation, inhibition of Mek-1 kinase and decreased phospho-extracellular signal-regulated kinase (Erk)1/2 levels. ARA-211 inhibition of the Raf/Mek/Erk1/2 pathway is mediated by PKA and not exchange protein activated by cAMP (EPAC). ARA-211 is selective and suppresses P-Erk1/2 but not P-JNK, P-p38, P-Akt or P-STAT3 levels. beta2AR stimulation results in inhibition of anchorage-dependent and -independent growth, induction of apoptosis in vitro and tumor regression in vivo. beta2AR antagonists and constitutively active Mek-1 rescue from the effects of ARA-211, demonstrating that beta2AR stimulation and Mek kinase inhibition are required for ARA-211 antitumor activity. Furthermore, suppression of growth occurs only in human tumors where ARA-211 induces cAMP formation and decreases P-Erk1/2 levels. Thus, beta2AR stimulation results in significant suppression of malignant transformation in cancers where it blocks the Raf-1/Mek-1/Erk1/2 pathway by a cAMP-dependent activation of PKA but not EPAC.

• Authors: A E Carie, S M Sebti
• Journal: Oncogene (Oncogene) Vol. 26 Issue 26 Pg. 3777-88 (May 31 2007) ISSN: 0950-9232 [Print] England
• PMID: 17260025 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-2 Receptor Agonists
• Adrenergic beta-Agonists
• Ethanolamines
• Guanine Nucleotide Exchange Factors
• RAPGEF3 protein, human
• Receptors, Adrenergic, beta-2
• Cyclic AMP
• Proto-Oncogene Proteins c-raf
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 1
• pirbuterol

Topics

• Adrenergic beta-2 Receptor Agonists
• Adrenergic beta-Agonists (pharmacology)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclic AMP (metabolism)
• Ethanolamines (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (drug effects)
• Female
• Guanine Nucleotide Exchange Factors (drug effects, metabolism)
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• MAP Kinase Kinase 1 (drug effects)
• Mice
• Mice, Nude
• Neoplasms, Experimental (drug therapy, metabolism)
• Proto-Oncogene Proteins c-raf (drug effects)
• Receptors, Adrenergic, beta-2 (drug effects)
• Signal Transduction (drug effects)