GABAB receptor is a novel drug target for pancreatic cancer

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Abstract
BACKGROUND.: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death. Smoking, diabetes, and pancreatitis are risk factors. It has been shown that the growth of PDAC and pancreatic duct epithelial cells is regulated by beta‐adrenoreceptors (β‐ARs). The activity of β‐ARs in the central nervous system is counteracted by γ‐aminobutyric acid (GABA) via GABAB receptor‐mediated inhibition of adenylyl cyclase. The aim of the study was to investigate if GABABR inhibits β‐AR signaling in PDAC and pancreatic duct epithelial cells, thus blocking driving forces of cancer progression, such as cell proliferation and cell migration.METHODS.: Intracellular cAMP was measured by immunoassays, DNA synthesis by BrdU incorporation assays, activation of ERK1/2 by ERK activation assays, and Western blots and metastatic potential by cell migration assays in the human PDAC cell lines PANC‐1 and BXPC‐3 and immortalized human pancreatic duct epithelial cells HPDE6‐C7. The expression of norepinephrine, PKARIIα, and GABA in PDAC microarrays was assessed by immunohistochemistry.RESULTS.: Stimulation of the GABABR by GABA or baclofen inhibited isoproterenol‐induced cAMP signaling below base levels. ERK1/2 activity in response to isoproterenol was blocked by GABA, an effect enhanced by transient overexpression of the GABABR and abolished by GABABR knockdown. DNA synthesis and cell migration were stimulated by isoproterenol, responses blocked by GABA and baclofen. Norepinephrine and PKARIIα were overexpressed while GABA was underexpressed in human PDAC tissue arrays.CONCLUSIONS.: The data suggest the stimulation of GABABR signaling as a novel target for the treatment and prevention of pancreatic cancer. Cancer 2008. © 2007 American Cancer Society.

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