Wang Mingliang, Yu Kexun, Meng Futao, Wang Huizhen, Li Yongxiang
General Surgery Department, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, China.
Mol Med. 2025 Jan 6;31(1):3. doi: 10.1186/s10020-024-01062-9.
Several members of the NIMA-related kinase (NEK) family have been implicated in tumor progression; however, the role and underlying mechanisms of NEK8 in gastric cancer (GC) remain unclear. This study revealed a significant upregulation of NEK8 in GC, identifying it as an independent prognostic marker in patients with GC. Consistent with these findings, NEK8 silencing substantially impeded GC aggressiveness both in vitro and in vivo, while its overexpression produced the opposite effect. Gene Ontology enrichment analysis and metabolic profiling indicated that the impact of NEK8 on GC is primarily associated with reprogramming asparagine metabolism and modulating the mTORC1 pathway. Specifically, NEK8 knockdown suppressed asparagine synthesis by downregulating asparagine synthetase (ASNS) expression in GC cells. A strong correlation was observed between NEK8 levels and ASNS expression in human GC cells and tissue samples. Mechanistically, NEK8 directly interacts with ASNS, phosphorylating it at the S349 site, which inhibits its ubiquitination and subsequent degradation. Moreover, substituting the ASNS-S349 site with alanine abrogated the pro-tumorigenic effects of ASNS-WT overexpression. Additionally, asparagine was identified as an activator of the mTORC1 pathway, with reintroducing asparagine after NEK8 silencing restoring mTORC1 activity. Collectively, these findings demonstrate that NEK8-mediated asparagine synthesis and activation of the mTORC1 pathway play a critical role in promoting GC progression.
NIMA相关激酶（NEK）家族的几个成员与肿瘤进展有关；然而，NEK8在胃癌（GC）中的作用及潜在机制仍不清楚。本研究揭示了NEK8在GC中显著上调，将其确定为GC患者的独立预后标志物。与这些发现一致，NEK8沉默在体外和体内均显著阻碍了GC的侵袭性，而其过表达则产生相反的效果。基因本体富集分析和代谢谱分析表明，NEK8对GC的影响主要与天冬酰胺代谢重编程和调节mTORC1途径有关。具体而言，NEK8敲低通过下调GC细胞中天冬酰胺合成酶（ASNS）的表达来抑制天冬酰胺合成。在人GC细胞和组织样本中观察到NEK8水平与ASNS表达之间存在强相关性。机制上，NEK8直接与ASNS相互作用，在S349位点使其磷酸化，从而抑制其泛素化及随后的降解。此外，用丙氨酸替代ASNS的S349位点可消除ASNS-WT过表达的促肿瘤作用。此外，天冬酰胺被确定为mTORC1途径的激活剂，NEK8沉默后重新引入天冬酰胺可恢复mTORC1活性。总的来说，这些发现表明NEK8介导的天冬酰胺合成和mTORC1途径的激活在促进GC进展中起关键作用。
