Background: Pancreatic cancer is the fourth leading cause of cancer deaths with
rising incidence and a high mortality rate. Smoking, psychological stress, diabetes, pancreatitis
and alcohol abuse are known risk factors for pancreatic cancer.
Objective: Targeting G protein-coupled receptor signaling for the prevention and therapy of
Method: Review of published literature.
Results and Conclusion: All known risk factors for pancreatic cancer cause hyperactive
cyclic adenosine monophosphate (cAMP) signaling via cancer stimulating Gαs-coupled
beta-adrenergic and prostaglandin E2 receptors and/or by suppressing signaling via inhibitory
Gαi-coupled GABAB-receptors. Psychological stress in mice promotes the progression
of pancreatic cancer xenografts via stress neurotransmitter-mediated increase in betaadrenergic
signaling and suppression of GABA while stress reduction inhibits pancreatic
cancer by reversing these effects. The activation of Gαi-coupled GABAB-receptor signaling
by treatment with GABA, inhibition of beta-adrenergic signaling by a beta-blocker and/or
suppression of Gαs-coupled PGE2 receptor signaling by a cyclooxygenase (COX) inhibitor
prevent the development and progression of pancreatic cancer induced in hamsters by carcinogenic
nitrosamines and in transgenic mice. The re-purposing of cardiovascular therapeutics
(beta-blockers, COX-2 inhibitors, Ca2+-channel blockers) that inhibit betaadrenergic
and PGE2 signaling for pancreatic cancer intervention is problematic due to undesirable
side effects under chronic treatment protocols. To avoid such side effects while
effectively reducing excessive cAMP signaling, nutritional GABA supplementation or
positive allosteric modulators (PAMs) of Gαi-coupled receptors (GABAB-Rs) currently in
clinical trials for the treatment of addiction should be explored for pancreatic cancer intervention.