Azad Mahan Gholam, Russell Tiffany M, Gu Xuanling, Zhao Xiao, Richardson Vera, Wijesinghe Tharushi P, Babu Golap, Guo Xinnong, Kaya Busra, Dharmasivam Mahendiran, Deng Zhao, Richardson Des R
Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Queensland, Australia.
Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
J Biol Chem. 2025 May 14;301(7):110230. doi: 10.1016/j.jbc.2025.110230.
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 upregulate 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.
N-Myc下游调控基因1（NDRG1）及其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多种功能作用。这些蛋白质参与调节在癌症中经常失调的关键信号蛋白和信号通路，如表皮生长因子受体（EGFR）、磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）、肝细胞生长因子受体（c-Met）和Wnt信号通路。NDRG1是NDRG家族主要且研究充分的成员，通常被认为是一种转移抑制因子，可抑制转移的第一步，即上皮-间质转化。虽然NDRG1已得到充分研究，但新出现的证据表明，NDRG2、NDRG3和NDRG4在调节致癌信号和细胞稳态方面也发挥着重要作用。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。对NDRG家族进行药物靶向治疗是一种抗癌治疗策略。例如，二-2-吡啶基酮4,4-二甲基-3-硫代半卡巴腙（Dp44mT）和二-2-吡啶基酮-4-环己基-4-甲基-3-硫代半卡巴腙（DpC）已被广泛证明可上调NDRG1的表达，在多种癌症模型中导致转移抑制和肿瘤生长抑制。同样，靶向NDRG2可显示其促凋亡和抗增殖作用，尤其是在胶质母细胞瘤和结直肠癌中。本综述对NDRG家族的结构特征、调控机制和生物学功能及其在癌症和神经退行性疾病中的作用进行了全面分析。此外，还探讨了NDRG1-4作为肿瘤学治疗靶点的情况，重点关注诱导这些蛋白表达的抗癌药物的最新进展。还讨论了对未来研究和临床应用的意义。
