GABA B receptor is a novel drug target for pancreatic cancer.
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 (beta-ARs). The activity of beta-ARs in the central nervous system is counteracted by gamma-aminobutyric acid (GABA) via GABA B receptor-mediated inhibition of adenylyl cyclase. The aim of the study was to investigate if GABA B R inhibits beta-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, PKAR IIalpha, and GABA in PDAC microarrays was assessed by immunohistochemistry. RESULTS.: Stimulation of the GABA B R 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 GABA B R and abolished by GABA B R knockdown. DNA synthesis and cell migration were stimulated by isoproterenol, responses blocked by GABA and baclofen. Norepinephrine and PKAR IIalpha were overexpressed while GABA was underexpressed in human PDAC tissue arrays.


CONCLUSIONS
The data suggest the stimulation of GABA B R signaling as a novel target for the treatment and prevention of pancreatic cancer.
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D001418:Baclofen / Q000494:pharmacology; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D018682:GABA Agents / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D018682:GABA Agents; D018755:GABA Agonists; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001973:Bromodeoxyuridine; D001418:Baclofen; D007545:Isoproterenol