Suppression of NF- B activity by NDRG2 expression attenuates the invasive potential of highly malignant tumor cells

Abstract

Downregulation of the N-myc downstream-regulated gene 2 (NDRG2) gene is involved in the progression of aggressive forms of cancer, along with the poor prognosis of cancer patients. In the current study, we examined the effect of NDRG2 expression on the metastatic potential of HT1080 human fibrosarcoma and B16F10 murine melanoma cells in both in vitro and in vivo systems. In gelatin zymography, NDRG2 expression remarkably suppressed the matrix metalloproteinase (MMP)-9 activity and slightly inhibited MMP-2 activity of both cell lines. Tumor migration and invasion in vitro were significantly reduced by NDRG2 expression, and NDRG2 inhibited tumor cell proliferation in an anchorage-independent semisolid agar assay. Specifically, we found that NDRG2 affects invasion through suppression of nuclear factor kappa B (NF-kappaB) activity. In animal experiments, subcutaneously injected B16F10-NDRG2 cells showed delayed tumor growth compared with B16F10-mock cells. Furthermore, severe metastasis from primary tumor mass into the draining lymph nodes was observed after injection of B16F10-mock cells, but not with B16F10-NDRG2 cells. Pulmonary metastasis after intravenous injection of B16F10 cells was also reduced by NDRG2 expression. Intra- and peritumoral angiogenesis that is critical for the tumor growth and metastasis was clearly found in tumors after injection with B16F10-mock cells, whereas it was impaired in tumors after injection with B16F10-NDRG2 cells. Collectively, our data show that NDRG2 expression significantly suppresses tumor invasion by inhibiting MMP activities, which are regulated through the NF-kappaB signaling. Moreover, results from animal experiments provide evidence for the regulatory role of the NDRG2 gene in metastatic tumors.

Simvastatin induces NFκB/p65 down-regulation and JNK1/c-Jun/ATF-2 activation, leading to matrix metalloproteinase-9 (MMP-9) but not MMP-2 down-regulation in human leukemia cells

“…Kim et al [58] found that N-myc downstream-regulated gene 2 (NDRG2) suppressed MMP-9 expression but not MMP-2 expression in HT1080 human fibrosarcoma cells and B16F10 murine melanoma cells, and NDRG2 repressed NFκB/p65 activity but not AP-1 activity in these cells. The results obtained by Fong et al [54] revealed that simultaneous inactivation of NFκB/p65 and AP-1 suppressed MMP-2 expression in 12-O-tetradecanoylphorbol-13-acetate-treated human lung cancer A549 cells.…”

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). Although the clinical role and therapeutic effect of NDRG2 are still to be investigated, the present study will continue to improve our understanding of the biological profile and behavior of CRC and enhancing prognostic stratification of patients with the aim of developing individualized new treatments.…”

“…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). However, to our knowledge, no correlations of NDRG2 with relapse and prognosis has not been addressed in CRC yet.…”

Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis

“…Matrigel plug assay. Subconfluent A431 cells were harvested, washed twice, and resuspended in PBS at 7.5 × 10 7 cells/mL [31]. Aliquots of the cells (0.1 mL) were mixed with 0.4 mL of growth factor-reduced Matrigel (BD Biosciences, 356231) with or without Fc or Fc-TPP11 (10 mg/kg), and the mixture was immediately injected SC, into the right thigh of nude mice.…”