Targeting the Metastasis Suppressor NDRG1: A New Strategy for the Treatment of Pancreatic Cancer

Abstract

AimsThe metastasis suppressor, N‐myc downstream regulated gene‐1 (NDRG1), is negatively correlated with tumor progression in pancreatic cancer. Moreover, NDRG1 is an iron‐regulated gene that is markedly up‐regulated by cellular iron‐depletion using novel anti‐tumor agents such as the chelator, Dp44mT, in pancreatic cancer cells. However, the exact molecular function(s) of NDRG1 remain to be established.ResultsUsing gene‐array analysis together with NDRG1 over‐expression and silencing, we identified molecular targets of NDRG1 in 3 pancreatic cancer cell lines. For the first time, we demonstrate that NDRG1 up‐regulates neural precursor cell expressed developmentally down‐regulated 4‐like (NEDD4L) and GLI‐similar 3 (GLIS3). Further studies examining the down‐stream effects of NEDD4L led to the discovery that NDRG1 affects the transforming growth factor β (TGF‐β) pathway, leading to up‐regulation of two key tumor suppressor proteins, namely phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and mothers against decapentaplegic homolog 4 (SMAD4) in multiple cell lines. Moreover, NDRG1 inhibited the phosphatidylinositol 3‐kinase (PI3K) and Ras oncogenic pathways.ConclusionThe identified target genes of NDRG1 and their effect on the TGF‐â signaling pathway reveal its molecular function in pancreatic cancer and a novel therapeutic avenue.