Study On The Function And Mechanisms Of NDRG1in Epithelial-mesenchymal Transition And Metastasis Of Malignant Tumors

Molecular-targeted therapies have been a recent focus and show promising benefits interms of inhibiting cancer progression. N-myc downstream-regulated gene1(NDRG1) is apotent metastasis suppressor that markedly reduces metastasis of numerous tumorsincluding those of the colon and prostate.It has been previously demonstrated using colon and prostate cell-types that NDRG1over-expression inhibits the transforming growth factor-β (TGF-β)-induced epithelialmesenchymal transition (EMT) by maintaining E-cadherin and β-catenin at the cellmembrane. Also, NDRG1was shown to play a role in the Wnt/β-catenin pathway to inhibitthe EMT. However, the precise molecular mechanism involved in how NDRG1mediatesthe stabilization of β-catenin was unclear and requires elucidation.In the current investigation, we examined whether NDRG1could modulatephosphorylation and cellular localization of β-catenin in2different tumor cell lines, namelyDU145prostate cancer cells and the HT29colonic cancer cells. Firstly, our studydemonstrated that NDRG1could inhibit the phosphorylation of β-catenin at Ser33/37andThr41. The mechanism of inhibiting β-catenin phosphorylation at these latter3sites was mediated, at least in part, by the NDRG1-mediated up-regulation of the GSK3β-bindingprotein, FRAT1, which prevents the association of GSK3β with theAxin1/APC destructioncomplex and subsequent phosphorylation of β-catenin.Moreover, NDRG1was shown to increase non-phosphorylated β-catenin levels on theplasma membrane to promote cell-cell adhesion, inhibit β-catenin nuclear translocation andits ability to act as a transcription factor through its effect on p21activated kinase4(PAK4).Notably, it is well known that PAK4binds to β-catenin and acts as a transporter fortranslocation to the nucleus. However, after NDRG1over-expression, PAK4was shown tobe localized to the plasma membrane, while NDRG1silencing led to nuclear accumulationof PAK4. Additionally, NDRG1was demonstrated to inhibit the WNT/β-catenin pathwayby abgogating WNT-mediated β-catenin expression and TCF/LEF transcriptional activity.The current study is the first to elucidate the molecular mechanisms involved in theregulation of β-catenin by NDRG1. This is critical to understand in terms of the potent roleof NDRG1in preventing the EMT and tumor cell metastasis, and it uncovers the potentialof this latter protein as a therapeutic target for cancer therapy.