N-myc Downstream-Regulated Gene 2 (NDRG2) Function as a Positive Regulator of Apoptosis: A New Insight into NDRG2 as a Tumor Suppressor

Abstract

N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene that increases tumor sensitivity to anticancer drugs, slows tumor progression, and inhibits metastasis. NDRG2 is suppressed in various aggressive tumor positions, whereas NDRG2 expression is associated with patient prognosis, such as an improved survival rate. In this review, we summarize the tumor suppressor mechanism of NDRG2 and provide information on the function of NDRG2 concerning the susceptibility of cells to apoptosis. NDRG2 increases the susceptibility to apoptosis in various physiological environments of cells, such as development, hypoxia, nutrient deprivation, and cancer drug treatment. Although the molecular and cell biological mechanisms of NDRG2 have not been fully elucidated, we provide information on the mechanisms of NDRG2 in relation to apoptosis in various environments. This review can assist the design of research regarding NDRG2 function and suggests the potential of NDRG2 as a molecular target for cancer patients.

Keywords: N-myc downstream-regulated gene 2; apoptosis; molecular target for tumor therapy; tumor suppressor.

Figure 1

Overview of NDRG2-mediated antitumor activity. GLUT, glucose transporter; LDHA, lactate dehydrogenase A; PKM2, pyruvate kinase M2; HK2, hexokinase 2; TCF/LEF, T-cell factor/lymphoid enhancer factor; STAT3, signal transducer and activator of transcription 3; ERK1/2, extracellular signal-regulated protein kinase; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; TGF-β, transforming Growth Factor-β; MMP, matrix metalloproteinase; EMT, epithelial-mesenchymal transition.

Figure 2

NDRG2 associated with p53-mediated apoptosis. NDRG2 is a novel p53-inducible target gene that is involved in p53-mediated apoptosis pathway. Unknown pathway (dotted arrow); DAPK1, death associated protein kinase 1; MDM2, mouse double minute 2; ERCC6, ERCC Repair 6; PARP, Poly (ADP-ribose) polymerase.

Figure 3

NDRG2 induces apoptosis to improve drug sensitivity in tumor cells. As an adaptor protein, NDRG2 increases the sensitivity of cells to apoptosis by mediating the PP2A-PTEN interaction and the PP2A-GSK3β interaction. NOX5 upregulation by NDRG2 enhances cisplatin-mediated apoptosis through ROS production. PP2A, protein phosphatase 2A; Mcl-1, myeloid leukemia cell differentiation protein-1; eIF, eukaryotic initiation factor; PKR, protein kinase R; NOX, NADPH oxidase; PTEN, phosphatase and tensin homolog).

Figure 4

NDRG2 functions in the sensitivity of tumor cells to metabolic stresses (red), hypoxia, glucose deprivation, or both (OGD, oxygen-glucose deprivation). Hif-1, hypoxia inducible factor-1; AMPK, AMP-activated protein kinase; ULK1, Unc-51 like autophagy activating kinase 1; mTOR, mammalian target of rapamycin.

Figure 5

Overview of NDRG2 function in various stimuli-mediated apoptosis.