Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Australia (Z.D., D.R.R.), and Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan (D.R.R.).
Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Australia (Z.D., D.R.R.), and Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan (D.R.R.)
Pharmacol Rev. 2023 Sep;75(5):1007-1035. doi: 10.1124/pharmrev.122.000795. Epub 2023 Jun 6.
Cancer is a leading cause of death worldwide, resulting in ∼10 million deaths in 2020. Major oncogenic effectors are the proto-oncogene family, which consists of three members including and As a pertinent example of the role of the Myc family in tumorigenesis, amplification of in childhood neuroblastoma strongly correlates with poor patient prognosis. Complexes between Myc oncoproteins and their partners such as hypoxia-inducible factor-1 and Myc-associated protein X (MAX) result in proliferation arrest and pro-proliferative effects, respectively. Interactions with other proteins are also important for N-Myc activity. For instance, the enhancer of zest homolog 2 (EZH2) binds directly to N-Myc to stabilize it by acting as a competitor against the ubiquitin ligase, SCF, which prevents proteasomal degradation. Heat shock protein 90 may also be involved in N-Myc stabilization since it binds to EZH2 and prevents its degradation. N-Myc downstream-regulated gene 1 (NDRG1) is downregulated by N-Myc and participates in the regulation of cellular proliferation via associating with other proteins, such as glycogen synthase kinase-3 and low-density lipoprotein receptor-related protein 6. These molecular interactions provide a better understanding of the biologic roles of N-Myc and NDRG1, which can be potentially used as therapeutic targets. In addition to directly targeting these proteins, disrupting their key interactions may also be a promising strategy for anti-cancer drug development. This review examines the interactions between the Myc proteins and other molecules, with a special focus on the relationship between N-Myc and NDRG1 and possible therapeutic interventions. SIGNIFICANCE STATEMENT: Neuroblastoma is one of the most common childhood solid tumors, with a dismal five-year survival rate. This problem makes it imperative to discover new and more effective therapeutics. The molecular interactions between major oncogenic drivers of the Myc family and other key proteins; for example, the metastasis suppressor, NDRG1, may potentially be used as targets for anti-neuroblastoma drug development. In addition to directly targeting these proteins, disrupting their key molecular interactions may also be promising for drug discovery.
癌症是全球主要的死亡原因之一，2020 年导致约 1000 万人死亡。原癌基因家族是主要的致癌效应因子，它由三个成员组成，包括 和 。作为 Myc 家族在肿瘤发生中的作用的一个恰当例子，在儿童神经母细胞瘤中扩增与患者预后不良强烈相关。Myc 癌蛋白与其伙伴（如缺氧诱导因子-1 和 Myc 相关蛋白 X（MAX））之间的复合物分别导致增殖停滞和促增殖作用。与其他蛋白质的相互作用对 N-Myc 活性也很重要。例如，Zeste 同源物 2（EZH2） enhancer 直接与 N-Myc 结合，通过充当与泛素连接酶 SCF 的竞争物来稳定它，从而防止蛋白酶体降解。热休克蛋白 90 也可能参与 N-Myc 稳定，因为它与 EZH2 结合并防止其降解。N-Myc 下游调节基因 1（NDRG1）被 N-Myc 下调，并通过与其他蛋白质（如糖原合酶激酶-3 和低密度脂蛋白受体相关蛋白 6）结合参与细胞增殖的调节。这些分子相互作用提供了对 N-Myc 和 NDRG1 生物学作用的更好理解，这可能被用作治疗靶点。除了直接靶向这些蛋白质之外，破坏它们的关键相互作用也可能是开发抗癌药物的一种很有前途的策略。这篇综述检查了 Myc 蛋白与其他分子之间的相互作用，特别关注 N-Myc 和 NDRG1 之间的关系以及可能的治疗干预措施。 意义声明：神经母细胞瘤是最常见的儿童实体肿瘤之一，五年生存率令人沮丧。这个问题使得发现新的、更有效的治疗方法势在必行。主要致癌驱动因子 Myc 家族和其他关键蛋白之间的分子相互作用；例如，转移抑制因子 NDRG1，可能潜在地用作神经母细胞瘤药物开发的靶点。除了直接靶向这些蛋白质之外，破坏它们的关键分子相互作用也可能是药物发现的一个很有前途的方向。
