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

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.

NEDD4 promotes cell growth and motility in hepatocellular carcinoma

“…Among these UPS members, the E3 ubiquitin ligase possesses a high variability of their components and interacts directly with ubiquitin substrates and determines the substrate specificity [17]. Neuronally expressed developmentally downregulated 4 (NEDD4, often known as NEDD4-1), a homologue to E6-AP C-terminus (HECT) family of E3 ubiquitin ligase, plays a critical role in the development and progression of many human cancers [18][19][20][21]. Amodio et al demonstrated that NEDD4 facilitated non-smallcell lung carcinomas (NSCLC) cell lines proliferation through inactivation of PTEN [22].…”

Unraveling the Potential Role of NEDD4-like E3 Ligases in Cancer

“…NEDD4 appears to be important in promoting HCC proliferation and spread through the stimulation of the PTEN/PI3K/Akt signaling pathway [ 111 ]. In PANC-1 pancreatic ductal adenocarcinoma (PDAC) cells, NEDD4 depletion suppresses cell growth partially by regulating the PTEN/Akt signaling pathway [ 112 ]. In addition, downregulation of NEDD4 suppresses proliferation of RT4 BCa cells.…”

Regulation of Notch signaling by E3 ubiquitin ligases

“…TRAF6 is a member of TNF pathway and more direct involvement of TNF signaling has been often linked with these disorders. Deregulation in another E3 ligase namely NEDD4 was observed in different types of cancers [147,148] as well as neuronal hyperactivity and seizures [149]. Interestingly, Imai et al…”

“…TRAF6 is a member of TNF pathway, and more direct involvement of TNF signaling has been often linked with these disorders. Deregulation in another E3 ligase, namely NEDD4, was observed in different types of cancers [144,145] and neuronal hyperactivity and seizures [146]. Interestingly, Imai et al (2015) have identified a new HECT-type E3 ligase, HERC2 that forms a complex with LRRK2, a key molecule involved in Parkinson's disease pathogenesis, and an adaptor-like protein Neurl4 to promote endosomal recycling of Notch ligand Delta-like 1/Delta to the membrane.…”