Pancreatic cancer (PDAC) has a mortality near 100%. Investigations conducted in our laboratory were the first to implicate Gs-protein coupled beta-adrenoreceptors (beta-ARs) in the regulation of adenocarcinomas of the lung and pancreas. Our studies showed that the proliferation of cell lines derived from human PDAC and their normal cells of origin, pancreatic duct epithelial cells, is stimulated by agonists for beta-ARs by signaling via cAMP/PKA/CREB and PKA-dependent transactivation of the EGFR. Other laboratories subsequently found that beta-AR agonists also stimulate migration and invasiveness of cancer of the colon, breast, prostate, and ovary as well as vascular endothelial growth factor and metalloproteinases in nasopharyngeal carcinoma. A novel concept is thus emerging of beta-adrenergic hyper stimulation as an important factor in the development of the most common human cancers, including PDAC. However, the cancerstimulating role of these receptors remains undetected when anti-cancer agents are tested in a controlled in vitro environment devoid of beta-adrenergic agonists or in xenographs of mice unchallenged by hyper stimulation of beta-adrenoreceptors. This may be one reason so many agents show great promise in preclinical tests but then disappoint in clinical trials.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. In the brain, GABA counteracts the stimulatory actions of epinephrine and norepinephrine, the physiological agonists for beta-ARs, via stimulation of the Gi-coupled GABA-BR. Two risk factors for PDAC, diabetes and pancreatitis, reduce the local availability of GABA by reducing the number of islet beta cells, the main source of GABA in the pancreas. Smoking, a third risk factor for PDAC, causes nicotine-induced release of epinephrine and nor-epinephrine, resulting in beta-adrenoreceptor hyper stimulation. The resulting predominance of stimulatory beta-adrenergic signaling over inhibitory GABA signaling, in our view, acts as a major driving force in the development of PDAC. In support of this hypothesis, our data show that GABA and the selective GABA-BR agonist baclophen completely block isoproterenol-induced cAMP signaling and ERK1/2 activation as well as DNA synthesis in PDAC cell lines and pancreatic duct epithelia. GABA-BR1gene knockdown by transfection with GABA-BR1 stealth RNAi completely blocked the inhibitory effects of GABA while over-expression of GABA-BR1 by transfection with GABA-BR1 cDNA enhanced the inhibitory actions of GABA. GABA and baclophen also completely inhibited isoproterenol-induced migration of PDAC cells. Our data suggest the GABA-BR as a novel drug target for the treatment and prevention of PDAC, a strategy that may also be applicable to other cancers stimulated by beta-ARs.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA