Abstract
AimTo determine the regulation and function of the neural precursor cell expressed developmentally down regulated protein 4 (NEDD4) in PDAC and to determine its dependency on phosphatase and tensin homolog (PTEN) and PI3K/AKT signaling.MethodsWe investigated the expression of NEDD4 and the tumor suppressor PTEN in normal immortalized human pancreatic duct epithelial cell line and pancreatic adenocarcinoma (PDAC) cell lines. We further evaluated whether RNAi-mediated depletion of NEDD4 can attenuate PDAC cell proliferation and migration. We subsequently determined the crosstalk between NEDD4 expression and the PTEN/PI3K/AKT signaling pathway. Finally, we determined the mechanism behind differential NEDD4 protein expression in pancreatic cancer.ResultsThe expression of NEDD4 was heterogeneous in PDAC cells, but was significantly higher compared to normal pancreatic ductal epithelial cells. Analogically, PTEN was decreased in the PDAC cells. A combination of MTT assay, wound healing migration assay, and transwell invasion assays confirmed that depletion of NEDD4 decreased the proliferation and migration ability of PDAC cells. Western blot and immunofluorescence results revealed that NEDD4 could affect PTEN/PI3K/AKT signaling pathway in PDAC cells. Polysomal profiling revealed that higher NEDD4 protein expression in PDAC cells was due to undefined mechanism involving translational activation.ConclusionsOur results reveal a novel mechanism of upregulation of NEDD4 expression in PDAC. Our findings indicate that NEDD4 potentially plays a critical role in activating the PI3K/AKT signaling pathway by negatively regulating PTEN levels in PDAC cells, which promotes pancreatic cancer cell proliferation and metastasis. Therefore, NEDD4 may be a potential therapeutic target in PDAC.
Highlights
Pancreatic cancer causes an estimated 227,000 deaths per year worldwide [1,2,3]
We observed that the expression of both proteins was highly heterogeneous in the Pancreatic ductal adenocarcinoma (PDAC) cell lines, with highest NEDD4 expression noted in the PANC-1 cell line (Figure 1A)
NEDD4 expression was higher in all the PDAC cell lines compared to the HPDE6c7 cell line
Summary
Pancreatic cancer causes an estimated 227,000 deaths per year worldwide [1,2,3]. Pancreatic ductal adenocarcinoma (PDAC) is the most common histological type of pancreatic cancer [1] presenting with a highly invasive and metastatic phenotype, which in turn is often responsible for treatment failure and an extremely poor clinical prognosis [3, 4]. It is important to identify prognostic and diagnostic markers that can be clinically implemented for optimized treatment strategies for pancreatic cancer patients. NEDD4 was initially identified as a critical protein in regulating neuronal function and plasticity in the brain [7]. Since NEDD4 itself is regulated by ubiquitination, phosphorylation and other posttranslational modifications, further evidence described the involvement of aberrant NEDD4 expression in cells with damages in the regulatory ubiquitination process. These aberrations lead to malignant transformations, underlying the significance of NEDD4 in tumorigenesis and cancer development [8, 9]
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