Metastasis suppressor, NDRG1, mediates its activity through signaling pathways and molecular motors

Abstract

The metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), is negatively correlated with tumor progression in multiple neoplasms, being a promising new target for cancer treatment. However, the precise molecular effects of NDRG1 remain unclear. Herein, we summarize recent advances in understanding the impact of NDRG1 on cancer metastasis with emphasis on its interactions with the key oncogenic nuclear factor-kappaB, phosphatidylinositol-3 kinase/phosphorylated AKT/mammalian target of rapamycin and Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways. Recent studies demonstrating the inhibitory effects of NDRG1 on the epithelial-mesenchymal transition, a key initial step in metastasis, TGF-β pathway and the Wnt/β-catenin pathway are also described. Furthermore, NDRG1 was also demonstrated to regulate molecular motors in cancer cells, leading to inhibition of F-actin polymerization, stress fiber formation and subsequent reduction of cancer cell migration. Collectively, this review summarizes the underlying molecular mechanisms of the antimetastatic effects of NDRG1 in cancer cells.

Serum Glucocorticoid–Regulated Kinase 1 Blocks CKD–Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3

“…Other reports are consistent with the finding that NDRG1 is phosphorylated by SGK-1. 19,32 Others report that phosphorylation of NDRG1 inhibits Smad-induced epithelial-mesenchymal transition. 20,32 Phosphorylation of NDRG1 also can inhibit NF-kB transcriptional activities and the expression of CXC chemokines.…”

“…19,32 Others report that phosphorylation of NDRG1 inhibits Smad-induced epithelial-mesenchymal transition. 20,32 Phosphorylation of NDRG1 also can inhibit NF-kB transcriptional activities and the expression of CXC chemokines. 18 Thus, phosphorylated NDRG1 not only suppresses inflammation but also, prevents muscle atrophy.…”

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).…”

Microenvironmental Influences on Metastasis Suppressor Expression and Function during a Metastatic Cell’s Journey

“…Loss of NDRG1 expression is generally correlated with an increase in cancer invasion and metastasis [153]. NDRG1 is associated with the cycling of E-cadherin to the cell surface, suggesting a role in reversing the invasive phenotype upon colonization of a new tissue [154].…”

“…NDRG1 also has the capacity to block the Ras/Raf and NFkB pathways, attenuating proliferation and down-regulating invasive phenotypes [153]. NDRG1 has also been implicated in blocking cellular motility by inhibiting g-actin-ARP2/3 polymerization to generate stress fibers, and the inhibition of ROCK to block formation of myosin light chain complexes for contractile motion [153].…”