NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states

Abstract

N-myc downstream-regulated gene 1 (NDRG1) is an intracellular protein that is induced under a wide variety of stress and cell growth-regulatory conditions. NDRG1 is up-regulated by cell differentiation signals in various cancer cell lines and suppresses tumor metastasis. Despite its specific role in the molecular cause of Charcot-Marie-Tooth type 4D disease, there has been more interest in the gene as a marker of tumor progression and enhancer of cellular differentiation. Because it is strongly up-regulated under hypoxic conditions, and this condition is prevalent in solid tumors, its regulation is somewhat complex, governed by hypoxia-inducible factor 1 alpha (HIF-1alpha)- and p53-dependent pathways, as well as its namesake, neuroblastoma-derived myelocytomatosis, and probably many other factors, at the transcriptional and translational levels, and through mRNA stability. We survey the data for clues to the NDRG1 gene's mechanism and for indications that the NDRG1 gene may be an efficient diagnostic tool and therapy in many types of cancers.

NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability

“…NDRG1, also known as DRG1, CAP43, RIT42, RTP, and PROXY-1, was first described as differentiation-related gene 1 (18,19). NDRG1 encodes the 46-kDa protein, NDRG1, which is highly conserved among multicellular organisms and is ubiquitously expressed in tissues in response to cellular stress (20). Prior studies demonstrated that NDRG1 is necessary but not sufficient for p53-mediated apoptosis (21) and may play a role in spindle organization, as NDRG1 has been shown to colocalize with centrosomes (22).…”

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

“…Hence, NDRG1 is a promising prognostic indicator and molecular target for these cancers (14), which represent some of the most common and fatal neoplastic conditions. The molecular functions of NDRG1 have been the subject of increasing interest in recent years, with studies demonstrating that this metastasis suppressor is involved in numerous signaling pathways that regulate cancer cell proliferation, invasion, angiogenesis, and migration (7,9,14,15). Specifically, NDRG1 inhibited the oncogenic RAS, c-Src, phosphatidylinositol 3-kinase (PI3K), WNT, ROCK1/pMLC2, and nuclear factor -light chain enhancer of activated B cell (NF-B) pathways, while promoting expression of key tumor-suppressive molecules such as phosphatase and tensin homolog, E-cadherin, and mothers against decapentaplegic homolog 4 (SMAD4) (4, 6, 8, 16 -20).…”

KAI1 Gene Is Engaged in NDRG1 Gene-mediated Metastasis Suppression through the ATF3-NFκB Complex in Human Prostate Cancer

“…Recent studies demonstrated that the NDRG1 gene is controlled by a variety of factors and stimuli related to cancer progression, including oncogenes, tumor suppressors, hypoxic microenvironment, and hormone dysregulation (30,31). Clinical studies also provided compelling evidence that reduced expression of the NDRG1 gene was significantly associated with poor overall survival rate in pancreatic ductal adenocarcinoma, glioma, prostate, breast, and colorectal cancers (32).…”