The E3 ubiquitin ligase NEDD4 is translationally upregulated and facilitates pancreatic cancer

Aim: To 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. Methods: We 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 RNA-imediated 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. Results: The 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. Conclusions: Our 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.