Targeting neddylation in cancer.
Targeting neddylation in cancer.
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靶向癌症中的neddylation。
DOI：
10.1093/neuonc/noac159
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发表时间：
2022
期刊：
影响因子：
15.9
通讯作者：
Cheng,Shi-Yuan
中科院分区：
文献类型：
--
作者：
Goenka,Anshika;Cheng,Shi-Yuan
自从发现泛素化途径以来，已经鉴定出涉及泛素样蛋白 (UBL) 共价蛋白缀合的同源途径。 1 NEDD8（神经元前体细胞表达的发育下调蛋白 8）就是这样一种 UBL，它通过可逆共价缀合（称为 neddylation）的翻译后修饰与底物蛋白缀合。 Neddylation 被证明可以调节包括癌症在内的多种生物过程。 2 与泛素修饰一样，neddylation 涉及通过 E1 NEDD8 激活酶 (NAE) 激活 NEDD8，然后将其转移至两种泛素结合酶 UBE2M 或 UBE2F 中的任一个，最终 NEDD8 通过底物特异性 E3 连接酶 RBX1/2 或 DCN1 的活性转移至目标蛋白的赖氨酸残基。 2 这一过程的一个例子是通过 NEDD8 缀合激活 Cullin-RING 连接酶 (CRL) 的 Cullin 亚基，Cullin-RING 连接酶是最大的 E3 泛素连接酶家族。研究发现 CRL 在癌症中过度表达并促进癌症进展，因此针对 Culin neddylation 是一种有吸引力的治疗策略。 2 2009 年，发现了一种有效的 NAE 小分子抑制剂，名为 MLN4924（又名 pevonedistat），它通过形成共价 NEDD8-MLN4924 加合物来抑制 neddylation 的第一步，从而阻断随后的 NAE 活性。 2 此后，MLN4924 被证明可有效调节多种细胞过程，包括 S 期缺陷、诱导自噬和细胞凋亡、抑制 Wnt 信号传导，以及通过靶向促癌斑点型 POZ 蛋白 (SPOP) E3 连接酶来诱导癌细胞中谷氨酰胺的摄取。 3, 4 迄今为止，已有 40 多项临床试验开始研究 MLN4924 的疗效，而已完成的临床试验则认为其使用安全可行。 2 neddylation 通路被发现在包括胶质母细胞瘤 (GBM) 在内的多种实体瘤中被激活。 2 在本期《神经肿瘤学》中，Ferdosi 等人 5 证明，具有完整 PTEN 肿瘤抑制基因的 GBM 临床前模型子集对 neddylation 抑制剂 MLN4924 敏感。约 40% 的 GBM 患者中 PTEN 缺失，导致 GBM 细胞中 PI3K-AKT 信号传导不受控制，从而导致细胞存活机制上调。一项研究表明，表皮生长因子受体 (EGFR) 抑制剂对 PTEN 具有类似的依赖性，其中 PTEN 的缺失或突变通过上调 PI3K/AKT 信号传导，赋予 GBM 对 EGFR 抑制剂的耐药性。 6 在确定 MLN4924 在 GBM 细胞系中的敏感性差异后，Ferdosi 等人采用 RNA 测序和鸟枪法蛋白质组学来确定敏感和耐药 GBM 细胞系中与 MLN4924 治疗相关的途径。 RNA-seq 数据显示，PTEN 信号传导是 MLN4924 敏感 GBM 细胞中富集的主要途径，其次是与细胞周期检查点、DNA 复制、染色体调控以及基线和治疗期间的染色质动态途径相关的途径，已知这些途径与野生型 PTEN 的功能相关。因此，之前的报告表明，抑制 DNA 损伤修复途径和染色质动力学途径会降低 MLN4924 在癌细胞中的功效。 2 虽然基于细胞的筛选已经确定了使细胞对新定义的抑制剂敏感的途径，但在这项研究中，作者将这些失调的途径与主调节基因 PTEN 的存在相关联，该基因的表达和相关特征可以作为患者的生物标志物……
Since the discovery of the ubiquitinylation pathway, homologous pathways have been identified which involve covalent protein conjugation by ubiquitin-like proteins (UBL). 1 NEDD8 (neuronal precursor cell-expressed developmentally downregulated protein 8) is one such UBL which gets conjugated to substrate proteins through a reversible covalent conjugation, post-translational modification called neddylation. Neddylation was shown to regulate diverse biological processes including cancer. 2 Like ubiquitin modification, neddylation involves the activation of NEDD8 through the E1 NEDD8-activating enzyme (NAE), which is then transferred to either of the two ubiquitin-conjugating enzymes UBE2M or UBE2F, and ultimately NEDD8 gets transferred to a lysine residue of the target protein through the activity of a substratespecific E3 ligase, RBX1/2, or DCN1. 2 One example of this process is the activation of the Cullin subunit of the Cullin-RING ligases (CRLs), the largest family of E3 ubiquitin ligases, by NEDD8 conjugation. CRLs are found to be overexpressed in cancers and contribute to cancer progression, and thus targeting Culin neddylation was an attractive therapeutic strategy. 2 In 2009, a potent small molecule inhibitor of NAE, named MLN4924 (aka pevonedistat) was discovered, which inhibits the first step of neddylation by forming a covalent NEDD8-MLN4924 adduct, thereby blocking the ensuing NAE activity. 2 Since then, MLN4924 has proved to be effective in modulating multiple cellular processes, including S-phase defects, induction of autophagy and apoptosis, inhibiting Wnt signaling, and induction of glutamine uptake in cancer cells by targeting the cancerpromoting Speckle-type POZ protein (SPOP) E3 ligase. 3, 4 To date, more than 40 clinical trials have started accrual to investigate MLN4924 efficacy while completed ones have deemed it to be safe and feasible for use. 2 The neddylation pathway is found to be activated in several solid tumors including Glioblastoma (GBM). 2 In this issue of Neuro-Oncology, Ferdosi et al 5 have demonstrated that a subset of GBM preclinical models with the intact PTEN tumor suppressor gene are susceptible to the neddylation inhibitor MLN4924. PTEN is deleted in~ 40% of GBM patients which results in uncontrolled PI3K-AKT signaling in GBM cells, thus causing an upregulation in cell survival mechanisms. One study has shown a similar dependence of epidermal growth factor receptor (EGFR) inhibitors on PTEN, wherein loss or mutation of PTEN confers resistance to EGFR inhibitors in GBM by upregulation of PI3K/AKT signaling. 6 Upon establishing the differential sensitivity of MLN4924 in GBM cell lines, Ferdosi et al resorted to RNA sequencing and shotgun proteomics to identify pathways associated with MLN4924 treatment in the sensitive and resistant GBM cell lines. RNA-seq data showed PTEN signaling to be the leading pathway enriched in MLN4924-sensitive GBM cells, followed by pathways related to cell cycle checkpoint, DNA replication, chromosome regulation, and chromatin dynamic pathways at baseline and through treatment and which are known to be associated functions of wild-type PTEN. Accordingly, previous reports have shown that inhibiting DNA damage repair pathways and chromatin dynamics pathways, reduced the efficacy of MLN4924 in cancer cells. 2 While cell-based screenings have identified pathways that make the cells susceptible to newly defined inhibitors, in this study the authors correlate these dysregulated pathways to the presence of a master regulator gene—PTEN—the expression and associated signatures of which could serve as biomarkers in patient …