Integrin β1 promotes gemcitabine resistance in pancreatic cancer through Cdc42 activation of PI3K p110β signaling

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignancies with very poor prognosis due to its broad resistance to chemotherapy. Our previous study showed that integrin beta 1 expression is upregulated in PDAC and confers gemcitabine resistance in PDAC cells via the signaling pathway including Cdc42 and AKT activation. But the accurate signal transductions are not clear. Here, we aimed to illuminate the signal transductions of integrin 01 in the acquisition of gemcitabine resistance in PDAC. Drug-resistance (DR) cells from AsPC-1 parent cell line (PCL) were selected. Integrin beta 1 expression was determined using western blot assay. Changes in drug response and the activity of phosphatidylinositol 3-kinase (PI3K) signaling after knockdown of integrin beta 1, Cdc42 or p110 beta were evaluated using MTT, cleaved caspase-3 immunofluorescence and western blot assay. Western blot assays also detected the variations in Cdc42 activity and p110 beta expression after integrin 01 knockdown. The interaction between Cdc42 and p110 beta was determined by Glutathione S-transferase (GST) pull-down assay. The results showed that integrin beta 1 expression was upregulated in DR-AsPC-1 cells, and integrin beta 1 knockdown significantly decreased the activity of Cdc42, a target molecule of integrin beta 1, and p110 beta expression. Knockdown of anyone of integrin beta 1, Cdc42 and p110 beta inhibited the activity of PI3K signaling, and sensitized DR-AsPC-1 cells to gemcitabine. GST pull-down assay showed that GTP-Cdc42 interacted with p110 beta. Collectively, these data indicated that integrin beta 1 promoted gemcitabine resistance in PDAC through Cdc42 activation of PI3K p110 beta signaling. In vivo experiments also confirmed this conclusion. These findings contribute to a better understanding the molecular mechanism of chemoresistance and facilitate the development of more targeted and effective treatment strategy for PDAC. (C) 2018 Elsevier Inc. All rights reserved.