Bidirectional Regulation between NDRG1 and GSK3β Controls Tumor Growth and Is Targeted by Differentiation Inducing Factor-1 in Glioblastoma
Bidirectional Regulation between NDRG1 and GSK3β Controls Tumor Growth and Is Targeted by Differentiation Inducing Factor-1 in Glioblastoma
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DOI：
10.1158/0008-5472.can-19-0438
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发表时间：
2020-01-15
期刊：
影响因子：
11.2
通讯作者：
Ono, Mayumi
中科院分区：
文献类型：
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作者：
Ito, Hiroshi;Watari, Kosuke;Ono, Mayumi
胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤之一，开发有效和选择性的治疗方法需要确定关键调节 GBM 存活和增殖的分子途径。先前的研究报道，N-myc 下游调节基因 1 (NDRG1) 的表达失调会影响包括神经胶质瘤在内的各种类型癌症患者的肿瘤生长和临床结果。在这里，我们发现肿瘤中 NDRG1 的高水平表达与 GBM 患者更好的预后显着相关。 GBM 细胞中 NDRG1 的缺失会上调 GSK3 β 水平并促进细胞增殖，而 GSK3 β 的选择性抑制剂可以逆转这种情况。相比之下，NDRG1 过表达通过蛋白酶体降解降低 GSK3 β 水平并抑制 AKT 和 S6 细胞生长信号传导以及细胞周期信号传导途径，从而抑制 GBM 细胞的生长。相反，GSK3 β 磷酸化 NDRG1 C 端结构域中的丝氨酸和苏氨酸位点，并限制 NDRG1 的蛋白质稳定性。此外，用分化诱导因子-1（一种源自盘基网柄菌的小分子）处理可增强 NDRG1 表达，降低 GSK3 β 表达，并在体外和体内发挥显着的 NDRG1 依赖性抗肿瘤作用。总而言之，这项研究揭示了 NDRG1 抑制 GBM 增殖和进展的新分子机制。因此，我们的研究将 NDRG1/GSK3 β 信号通路确定为 GBM 中的关键生长调节程序，并表明增强 GBM 中的 NDRG1 表达是开发抗 GBM 疗法的有效策略。意义：本研究确定 NDRG1 是胶质母细胞瘤细胞生长的有效内源性抑制剂，表明 NDRG1 靶向疗法针对胶质母细胞瘤的临床益处。
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 GSK3 beta levels and promoted cell proliferation, which was reversed by selective inhibitors of GSK3 beta. In contrast, NDRG1 overexpression suppressed growth of GBM cells by decreasing GSK3 beta levels via proteasomal degradation and by suppressing AKT and S6 cell growth signaling, as well as cell-cycle signaling pathways. Conversely, GSK3 beta 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 GSK3 beta 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/GSK3 beta 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.