Norepinephrine mediates adrenergic receptor transcription and oncogenic gene expression in pancreatic ductal adenocarcinoma

Adrenergic stimulation of β₂ receptors has shown to increase pancreatic ductal adenocarcinoma (PDAC) proliferation and migration in an in vitro setting; however, the role of α₁ receptors in these adrenergic signaling pathways is unclear. Previous research has suggested that the MAPK signaling pathway is upregulated in response to β-adrenergic signaling, but other signaling pathways and downstream targets of mutant KRAS have yet to be investigated. This study investigates the role of adrenergic signaling through α₁ and β-receptors in two human-derived PDAC cell lines, examining proliferation, wound healing, and protein expression after treatment with norepinephrine (NE) and in the presence of β and α₁-receptor antagonism. Using RT-qPCR, the expression of adrenergic receptors and downstream KRAS effector proteins was evaluated. We found that NE has varying effects on proliferation and wound healing in different PDAC cell lines. Moreover, adrenergic receptor expression is under negative feedback control through α₁ signaling in both cell lines. Furthermore, NE decreases expression of MMP9 while also affecting expression of VIM, CCND1, mTOR, and rhoA. We demonstrate genotype dependent effects of adrenergic stimulation on downstream molecular signaling pathways in PDAC that are important for oncogenicity. Based on our findings, genotypic characterization of cell signaling pathways in PDAC may aid further research in effective therapeutics for PDAC.