Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing, China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Cancer Sci. 2024 Aug;115(8):2673-2685. doi: 10.1111/cas.16204. Epub 2024 May 27.
Aberrant signaling in tumor cells induces nonmetabolic functions of some metabolic enzymes in many cellular activities. As a key glycolytic enzyme, the nonmetabolic function of hexokinase 2 (HK2) plays a role in tumor immune evasion. However, whether HK2, dependent of its nonmetabolic activity, plays a role in human pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains unclear. Here, we demonstrated that HK2 acts as a protein kinase and phosphorylates IκBα at T291 in PDAC cells, activating NF-κB, which enters the nucleus and promotes the expression of downstream targets under hypoxia. HK2 nonmetabolic activity-promoted activation of NF-κB promotes the proliferation, migration, and invasion of PDAC cells. These findings provide new insights into the multifaceted roles of HK2 in tumor development and underscore the potential of targeting HK2 protein kinase activity for PDAC treatment.
肿瘤细胞中的异常信号转导诱导一些代谢酶在许多细胞活动中发挥非代谢功能。作为关键的糖酵解酶，己糖激酶 2（HK2）的非代谢功能在肿瘤免疫逃逸中发挥作用。然而，HK2 是否依赖其非代谢活性在人类胰腺导管腺癌（PDAC）肿瘤发生中发挥作用尚不清楚。在这里，我们证明 HK2 在 PDAC 细胞中作为蛋白激酶起作用，并在 T291 处磷酸化 IκBα，激活 NF-κB，NF-κB 进入细胞核并在缺氧下促进下游靶基因的表达。HK2 非代谢活性促进的 NF-κB 激活促进 PDAC 细胞的增殖、迁移和侵袭。这些发现为 HK2 在肿瘤发展中的多方面作用提供了新的见解，并强调了针对 HK2 蛋白激酶活性治疗 PDAC 的潜力。
