Abstract
The development of potent and selective therapeutic approaches to glioblastoma (GBM), one of the most aggressive primary brain tumors, requires identification of molecular pathways that critically regulate the survival and proliferation of GBM. Previous studies have reported that deregulated expression of N-myc downstream regulated gene 1 (NDRG1) affects tumor growth and clinical outcomes of patients with various types of cancer including glioma. Here, we show that high level expression of NDRG1 in tumors significantly correlated with better prognosis of patients with GBM. Loss of NDRG1 in GBM cells upregulated GSK3β levels and promoted cell proliferation, which was reversed by selective inhibitors of GSK3β. In contrast, NDRG1 overexpression suppressed growth of GBM cells by decreasing GSK3β levels via proteasomal degradation and by suppressing AKT and S6 cell growth signaling, as well as cell-cycle signaling pathways. Conversely, GSK3β phosphorylated serine and threonine sites in the C-terminal domain of NDRG1 and limited the protein stability of NDRG1. Furthermore, treatment with differentiation inducing factor-1, a small molecule derived from Dictyostelium discoideum, enhanced NDRG1 expression, decreased GSK3β expression, and exerted marked NDRG1-dependent antitumor effects in vitro and in vivo. Taken together, this study revealed a novel molecular mechanism by which NDRG1 inhibits GBM proliferation and progression. Our study thus identifies the NDRG1/GSK3β signaling pathway as a key growth regulatory program in GBM, and suggests enhancing NDRG1 expression in GBM as a potent strategy toward the development of anti-GBM therapeutics. SIGNIFICANCE: This study identifies NDRG1 as a potent and endogenous suppressor of glioblastoma cell growth, suggesting the clinical benefits of NDRG1-targeted therapeutics against glioblastoma.
Highlights
In 2016, the World Health Organization (WHO) revised the classification of glioma based on the presence of mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes and chromosome 1p/19q status [1]
We demonstrate that the differentiation inducing factor1 (DIF-1) induces a marked enhancement of N-myc downstream regulated gene 1 (NDRG1) expression, resulting in tumor growth suppression in vitro and in vivo
These results suggest that NDRG1 expression levels correlate with favorable prognosis in patients with GBM
Summary
In 2016, the World Health Organization (WHO) revised the classification of glioma based on the presence of mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes and chromosome 1p/19q status [1]. Glioblastoma (GBM), WHO grade IV and the most common and aggressive primary brain tumor, exhibits a high recurrence rate, and poor prognosis attributable to its invasive nature and resistance to therapy [2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Changes that drive the growth and survival of GBM cells remain unclear. Combination of standard therapy, irradiation, and temozolomide, with molecular-targeted drugs, such as EGFR, PI3K, or mTOR inhibitors, failed to improve the overall or progression-free survival in phase III clinical trials [2].
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