Loss of p21-activated kinase 4 (PAK4) suppresses pancreatic tumor progression and metastasis through regulating E-cadherin

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis with early and frequent metastasis. While p21-activated kinase 4 (PAK4) has been implicated in cell migration, and invasion, the molecular mechanisms in PDAC remain unknown. In this study, we found that PAK4 overexpression was correlated with poor survival in PDAC patients through analysis of TCGA data. PAK4-amplified PDAC cells showed enhanced mobility in contrast with wild-type. PAK4 knockdown in PAK4 amplified cells inhibited cell migration, invasion, and displacement by increased and stabilized E-cadherin, which was attributed to decreased activity of Cdc42. PAK4 knock-in in PAK4 wild-type models enhanced cell migration, invasion, and displacement by reduced E-cadherin through elevated Cdc42 activity. PAK4 bounded to E-cadherin, Cdc42, and p120ctn in immunoprecipitation. In confocal imaging, the colocalization of PAK4, E-cadherin, p120ctn, and Cdc42 was also identified. In an orthotopic PDAC mouse model, PAK4 knockdown decreased primary tumor size and occurrence of malignant ascites by activation of E-cadherin. Notably, in patients tissue specimens, inverse correlation on expression of PAK4 and E-cadherin were also shown. In conclusion, our study highlights that PAK4 promotes invasive and metastatic behavior by regulating E-cadherin in PDAC. PAK4 could be a potential therapeutic target for PDAC patients. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/594599v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1755a23org.highwire.dtl.DTLVardef@170b2a1org.highwire.dtl.DTLVardef@1df96edorg.highwire.dtl.DTLVardef@2dc46b_HPS_FORMAT_FIGEXP M_FIG C_FIG