Dysbindin promotes progression of pancreatic ductal adenocarcinoma via direct activation of PI3K

Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents a biggest challenge in clinic oncology due to its invasiveness and lack of targeted therapeutics. Our recent study showed that schizophrenia susceptibility factor dysbindin exhibited significant higher level in serum of PDAC patients. However, the functional relevance of dysbindin in PDAC is still unclear. Here, we show that dysbindin promotes tumor growth both in vitro and in vivo by accelerating the G1/S phase transition in cell cycle via PI3K/AKT signaling pathway. Mechanistically, dysbindin interacts with PI3K and stimulates the kinase activity of PI3K. Moreover, overexpression of dysbindin in PDAC is correlated with clinicopathological characteristics significantly, such as histological differentiation (P = 0.011) and tumor size (P = 0.007). Kaplan-Meier survival curves show that patients with high dysbindin expression exhibit poorer overall survival, compared to those with low dysbindin expression (P < 0.001). Multivariate analysis reveals that dysbindin is an independent prognostic factor for pancreatic ductal adenocarcinoma (P = 0.001). Thus, our findings reveal that dysbindin is a novel PI3K activator and promotes PDAC progression via stimulation of PI3K/AKT. Dysbindin therefore represents a potential target for prognosis and therapy of PDAC.

Analytically validated protein biomarkers of chronic pancreatitis and pancreatic cancer for potential clinical diagnosis with mass spectrometry

“…They identified dysbindin (DTNBP1) as the potential protein biomarker for the discrimination of PC ( n = 250) from CP ( n = 70) with AUC of 0.80 (sensitivity of 73.9% and specificity of 78.9) . The same team recently proved that dysbindin is an independent prognostic marker for PC …”

Dysbindin facilitates invasion and metastasis by promoting phosphorylation of ERK in epithelial ovarian cancer

“…International Publisher and progression and significantly correlated with patients' prognosis. In a recent study, dysbindin showed significant correlation with pancreatic cancer and promoted tumor proliferation in vitro and in vivo [4,11]. Thus, improved knowledge of functions in dysbindin may help understand biology and provide optimal strategies in human cancers.…”

“…The immunohistochemistry staining procedures were adopted, as was previously introduced [4]. Three independent pathologists firstly evaluated the H&E staining sections to confirm whether the specimens were EOC tissues.…”

“…Dysbindin (DTNBP1), a novel oncoprotein, has been reported to be a regulator of Akt signaling pathway [4]. Dysbindin has been demonstrated to be ubiquitously distributed in central nervous system and embryonic tissues [5].…”

Dynamic acetylation of the kinetochore-associated protein HEC1 ensures accurate microtubule–kinetochore attachment

“…FLAG-Aurora B kinases were subjected to an in vitro kinase assay using the 15-mer substrate peptide (WT, ERKVSLFG-KRTSGHG; RR, ERRVSLFGRRTSGHG; QQ, ERQVSLF-GQRTSGHG) and ATP as the substrates and the ADP assay buffer provided by the Amplite TM universal fluorimetric kinase assay kit *Red Fluorescence* (AAT Bioquest) as the kinase buffer. The produced ADP was quantified using the Amplite TM universal fluorimetric kinase assay kit according to the manufacturer's manuals (53)(54)(55)(56). The velocity of phosphorylation at a certain concentration of ATP and substrate peptide was calculated from the concentration of produced ADP, the concentration of kinase, and the reaction time.…”