ß2-adrenergic receptor drives the metastasis and invasion of pancreatic ductal adenocarcinoma through activating Cdc42 signaling pathway.

ABSTRACT

Recent investigations indicate that ß2-adrenergic receptor (ß2-AR) signaling may facilitate the progression of various tumors, whose underlying mechanisms remain largely elusive. In the present study, we showed that ß2-AR recruited Cdc42 in response to isoproterenol (ISO, a ß-AR selective agonist) exposure in pancreatic ductal adenocarcinoma (PDAC) cells. The association of ß2-AR and Cdc42 promoted the activation of Cdc42, as revealed by increased levels of Cdc42-GTP, and co-incubation with ß2-AR antagonist abrogated ISO-induced activation of Cdc42. ß2-AR-mediated Cdc42 activation further led to the phosphorylation of downstream PAK1, LIMK1 and Merlin. Furthermore, we showed that the activation of ß2-AR/Cdc42 signaling facilitated the migration and invasion of PDAC cells. In addition, ß2-AR and Cdc42 were overexpressed in PDAC specimens, compared with adjacent non-tumor tissues. High expression of ß2-AR and Cdc42 were correlated with lymph node metastasis and TNM stage in PDAC patients. Finally, we showed that overexpression of ß2-AR and Cdc42 were indicative of unfavorable prognosis in PDAC patients. Taken together, our findings suggested that ß2-AR might facilitate Cdc42 signaling to drive the migration and invasion of PDAC cells, consequently resulting in the metastasis and dismal prognosis of PDAC. These studies highlight targeting ß2-AR/Cdc42 signaling as a therapeutic strategy against PDAC.