NDRG2 suppresses cell proliferation through down‐regulation of AP‐1 activity in human colon carcinoma cells

Abstract

Recently, the anti-tumor activity of N-myc downstream-regulated gene 2 (NDRG2) was elucidated, but the molecular mechanism of how NDRG2 works as a tumor suppressor is not well known. To determine the function of NDRG2 as a tumor suppressor, we established stable cell lines expressing NDRG2 protein or its mutant forms, and studied their effects on tumor cell growth. Interestingly, constitutive expression of wild-type NDRG2 induced the growth retardation of SW620 colon carcinoma cells. Introduction of NDRG2 into SW620 cells induced the decrease of c-Jun phosphorylation at Ser63, followed by the attenuation of activator protein-1 (AP-1) function as a transcriptional activator. Subsequently, the down-regulation of cyclin D1, which is known as a major target for AP-1 transcription activator, resulted in cell cycle arrest at G1/S phase. Additionally, treatment of NDRG2-siRNA on NDRG2-expressing cells has induced the recovery of c-Jun phosphorylation and cyclin D1 expression. Cell proliferation of those cells was also increased compared with untreated cells. NDRG2 mutants of which the phosphorylation sites at C-terminal region were removed by deletion or site-directed mutagenesis have shown no effect on cyclin D1 expression and could not induce cell growth retardation. In conclusion, NDRG2 modulates intracellular signals to control cell cycle through the regulation of cyclin D1 expression via phosphorylation pathway.

FosB transcription factor regulates COX-2 expression in colorectal cancer cells without affecting PGE2 expression

“…A previous study by the present authors proposed FosB as an important transcription factor in CRC patients with high COX-2 tumor tissue expression, since FosB was overexpressed in these patients, comparing with patients who exhibited low COX-2 expression (19). FosB is a member of the AP-1 complex, which has been linked to malignant transformation in several types of cancer, and its components, including FosB, have important roles on cell proliferation (among other functions), which suggests their involvement in cancer development (27)(28)(29)(30). In the present study, the role of FosB on the COX-2/PGE2 axis was investigated.…”

Prediction of Colorectal Cancer Relapse and Prognosis by Tissue mRNA Levels of NDRG2

“…Recent studies have shown that NDRG2 could suppress cell proliferation through the regulation of cyclin D1 and TCF/b-catenin activity (19,20). NDRG2 was also reported to suppress NF-kB activity in order to inhibit carcinogenesis, invasion, and metastasis of human malignancy (21,22).…”

“…These data suggested that aberrant expression of NDRG2 in malignancy could serve as a tumor-suppressive role in carcinogenesis. Moreover, it is reported that NDRG2 could suppress cell proliferation possibly through the regulation of cyclin D1 and T-cell factor (TCF)/b-catenin activity (19,20). Recent study also showed that NDRG2 could suppress nuclear factor kappa B (NF-kB) activity, suggesting a possible mechanism for NDRG2 to participate in carcinogenesis and progression of human malignancy (21,22).…”

The effect of Ndrg2 expression on astroglial activation

“…As Ndrg2 was reported to have growth-inhibitory and apoptosis-inducing effects on various types of tumor cells (Deng et al, 2003, Kim YJ et al, 2009) as well as on hepatocytes (Yang et al, 2010), the effect of Ndrg2 on astroglial proliferation and apoptosis was analyzed using cultured astrocytes isolated from neonatal rats. Transfection of Ndrg2 siRNA (siNdrg2-1,…”

“…An increasing number of reports has demonstrated that Ndrg2 had inhibitory effects on the proliferation (Deng et al, 2003, Kim YJ et al, 2009 and invasion ) of tumor cells including glioblastoma. It was also reported that Ndrg2 regulated the production of certain secretory proteins in dendritic cells (Choi et al, 2007, Choi et al, 2010.…”