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Electrophoretic Delivery of γ-aminobutyric Acid GABA into Epileptic Focus Prevents Seizures in Mice
Published on: May 16, 2019
GABA B receptor is a novel drug target for pancreatic cancer
Hildegard M Schuller1, Hussein A N Al-Wadei, Mourad Majidi
1Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996, USA. hmsch@utk.edu
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.
Insights
Stimulating GABA B receptors (GABA B R) may offer a new approach to treat and prevent pancreatic cancer by inhibiting cell growth and migration. This study investigated GABA B R
Area of Science:
- Oncology
- Neuroscience
- Cell Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with known risk factors including smoking, diabetes, and pancreatitis.
- Beta-adrenoreceptors (beta-ARs) regulate the growth of PDAC and pancreatic duct epithelial cells.
- Gamma-aminobutyric acid (GABA) B receptors (GABA B R) inhibit beta-AR activity in the central nervous system.
Purpose of the Study:
- To determine if GABA B R activation inhibits beta-AR signaling in PDAC and pancreatic duct epithelial cells.
- To investigate the potential of targeting GABA B R to block cancer progression drivers like cell proliferation and migration.
Main Methods:
- Assessed intracellular cAMP, DNA synthesis, ERK1/2 activation, and cell migration in PDAC and pancreatic duct epithelial cell lines.
- Utilized immunoassays, BrdU incorporation, ERK activation assays, Western blots, and cell migration assays.
- Examined expression of norepinephrine, PKAR IIalpha, and GABA in PDAC tissue microarrays via immunohistochemistry.
Main Results:
- GABA or baclofen stimulation of GABA B R inhibited isoproterenol-induced cAMP signaling.
- GABA blocked isoproterenol-stimulated ERK1/2 activity, DNA synthesis, and cell migration.
- Norepinephrine and PKAR IIalpha were overexpressed, while GABA was underexpressed in human PDAC tissues.
Conclusions:
- GABA B R signaling plays a crucial role in regulating PDAC cell proliferation and migration.
- Stimulating GABA B R represents a potential novel therapeutic strategy for pancreatic cancer treatment and prevention.
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