NDRG1 and its Family Members: More than Just Metastasis Suppressor Proteins and Targets of Thiosemicarbazones.

IF 4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biological Chemistry Pub Date : 2025-05-14 DOI:10.1016/j.jbc.2025.110230

Mahan Gholam Azad,Tiffany Russell,Xuanling Gu,Xiao Zhao,Vera Richardson,Tharushi P Wijesinghe,Golap Babu,Xinnong Guo,Busra Kaya,Mahendiran Dharmasivam,Zhao Deng,Des R Richardson

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引用次数: 0

Abstract

N-Myc downstream regulated gene-1 (NDRG1) and the other three members of this family (NDRG2, 3, and 4) play various functional roles in the cellular stress response, differentiation, migration, and development. These proteins are involved in regulating key signaling proteins and pathways that are often dysregulated in cancer, such as EGFR, PI3K/AKT, c-Met, and the Wnt pathway. NDRG1 is the primary, well-examined member of the NDRG family, and is generally characterized as a metastasis suppressor that inhibits the first step in metastasis, the epithelial-mesenchymal transition. While NDRG1 is well-studied, emerging evidence suggests NDRG2, NDRG3, and NDRG4 also play significant roles in modulating oncogenic signaling and cellular homeostasis. NDRG family members are regulated by multiple mechanisms, including transcriptional control by hypoxia-inducible factors, p53, and Myc, as well as post-translational modifications such as phosphorylation, ubiquitination, and acetylation. Pharmacological targeting of the NDRG family is a therapeutic strategy against cancer. For instance, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) have been extensively shown to up-regulate NDRG1 expression, leading to metastasis suppression and inhibition of tumor growth in multiple cancer models. Similarly, targeting NDRG2 demonstrates its pro-apoptotic and anti-proliferative effects, particularly in glioblastoma and colorectal cancer. This review provides a comprehensive analysis of the structural features, regulatory mechanisms, and biological functions of the NDRG family and their roles in cancer and neurodegenerative diseases. Additionally, NDRG1-4 are explored as therapeutic targets in oncology, focusing on recent advances in anti-cancer agents that induce the expression of these proteins. Implications for future research and clinical applications are also discussed.

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NDRG1及其家族成员：不仅仅是转移抑制蛋白和硫代氨基脲的靶标。

N-Myc下游调控基因1 （NDRG1）和该家族的其他三个成员（NDRG2、3和4）在细胞应激反应、分化、迁移和发育中发挥着各种功能作用。这些蛋白参与调节在癌症中经常失调的关键信号蛋白和通路，如EGFR、PI3K/AKT、c-Met和Wnt通路。NDRG1是NDRG家族中被广泛研究的主要成员，通常被认为是一种转移抑制因子，可以抑制转移的第一步，即上皮-间质转化。虽然NDRG1已被充分研究，但新出现的证据表明，NDRG2、NDRG3和NDRG4也在调节致癌信号和细胞稳态中发挥重要作用。NDRG家族成员受多种机制调控，包括缺氧诱导因子、p53和Myc的转录控制，以及磷酸化、泛素化和乙酰化等翻译后修饰。NDRG家族的药理靶向是一种治疗癌症的策略。例如，在多种癌症模型中，二-2-吡啶基酮4,4-二甲基-3-硫代氨基卡巴酮（Dp44mT）和二-2-吡啶基酮-4-环己基-4-甲基-3-硫代氨基卡巴酮（DpC）已被广泛证明可上调NDRG1表达，从而抑制肿瘤转移和抑制肿瘤生长。同样，靶向NDRG2显示其促凋亡和抗增殖作用，特别是在胶质母细胞瘤和结直肠癌中。本文综述了NDRG家族的结构特征、调控机制、生物学功能及其在癌症和神经退行性疾病中的作用。此外，NDRG1-4作为肿瘤的治疗靶点被探索，重点关注诱导这些蛋白表达的抗癌药物的最新进展。对未来研究和临床应用的意义也进行了讨论。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry

自引率

4.20%

发文量

1233

期刊介绍： The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.