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.
From: Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA.
Oncogene
- Publish Date: May 2007
- ISSN: 0950-9232
- Volume: 26
- Issue: 26
- Pages: 3777-88
- Medium: Print
- Language: English
- Citation (JAMA): Carie A E, Sebti S M, et al. 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.. Oncogene May 2007;26:3777-88
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.
Mesh Headings (Keywords): Adrenergic beta-Agonists, Animals, Apoptosis, Blotting, Western, Cell Line, Tumor, Cell Proliferation, Cyclic AMP, Ethanolamines, Extracellular Signal-Regulated MAP Kinases, Female, Guanine Nucleotide Exchange Factors, Humans, Immunohistochemistry, In Situ Nick-End Labeling, MAP Kinase Kinase 1, Mice, Mice, Nude, Neoplasms, Experimental, Proto-Oncogene Proteins c-raf, Receptors, Adrenergic, beta-2, Signal Transduction
Check for Full Text / PubMed Unique Identifier (PMID): 17260025
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