Regulatory Role of G Protein-coupled Receptors in Pancreatic Cancer Development and Progression

Abstract

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 pancreatic cancer.

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.

Keywords: G protein-coupled receptors; Gαi-coupled GABAB-receptors; Gαs-coupled beta-adrenergic and PGE2-receptors; Pancreatic cancer; cAMP homeostasis..