Stress and obesity signaling converge on CREB phosphorylation to promote pancreatic cancer

Abstract One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the beta adrenergic receptor agonist isoproterenol rapidly stimulate CREB phosphorylation at Ser133 in human PDAC cells. Exposure to the non-selective beta adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551 blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser133. Mechanistically, norepinephrine induced CREB phosphorylation at Ser133 via PKA whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D (PKD). Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet (HFCD) that promotes early PDAC development were subjected to social isolation stress (SIS). We show that SIS induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in KC mice subjected to an obesogenic HFCD. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.