1. Bidirectional Regulation between NDRG1 and GSK3β Controls Tumor Growth and Is Targeted by Differentiation Inducing Factor-1 in Glioblastoma
- Author
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Tomohiro Shibata, Yukiko Nakahara, Mayumi Ono, Hiroaki Wakimoto, Tatsuya Abe, Kosuke Watari, Yuichi Murakami, Michihiko Kuwano, Tomofumi Miyamoto, Hiroto Izumi, and Hiroshi Ito
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,Pyridines ,Primary Cell Culture ,Cell Cycle Proteins ,Kaplan-Meier Estimate ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,Glioma ,Thiadiazoles ,medicine ,Humans ,Phosphorylation ,RNA, Small Interfering ,Protein kinase B ,Aged ,Cell Proliferation ,Aged, 80 and over ,Glycogen Synthase Kinase 3 beta ,Brain Neoplasms ,Protein Stability ,Cell growth ,Intracellular Signaling Peptides and Proteins ,Brain ,Middle Aged ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Differentiation-inducing factor ,Hexanones ,Pyrimidines ,030104 developmental biology ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Signal transduction ,Glioblastoma ,Signal Transduction - 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.
- Published
- 2020