Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway.
Cell Rep. 2020 Apr 14;31(2):107518. doi: 10.1016/j.celrep.2020.03.082.
The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) is overexpressed in several types of cancer, suggesting an additional function beyond its established role in the glycolytic pathway. We here report that PGAM1 is overexpressed in gliomas where it increases the efficiency of the DNA damage response (DDR) pathway by cytoplasmic binding of WIP1 phosphatase, thereby preventing WIP1 nuclear translocation and subsequent dephosphorylation of the ATM signaling pathway. Silencing of PGAM1 expression in glioma cells consequently decreases formation of γ-H2AX foci, increases apoptosis, and decreases clonogenicity following irradiation (IR) and temozolomide (TMZ) treatment. Furthermore, mice intracranially implanted with PGAM1-knockdown cells have significantly improved survival after treatment with IR and TMZ. These effects are counteracted by exogenous expression of two kinase-dead PGAM1 mutants, H186R and Y92F, indicating an important non-enzymatic function of PGAM1. Our findings identify PGAM1 as a potential therapeutic target in gliomas.
磷酸甘油酸变位酶 1（PGAM1）是一种代谢酶，在多种类型的癌症中过度表达，这表明其在糖酵解途径中的作用之外，还具有其他额外的功能。我们在这里报告称，PGAM1 在神经胶质瘤中过度表达，通过与 WIP1 磷酸酶的细胞质结合，提高了 DNA 损伤反应（DDR）途径的效率，从而阻止了 WIP1 的核转位以及随后 ATM 信号通路的去磷酸化。在神经胶质瘤细胞中沉默 PGAM1 的表达，随后会减少 γ-H2AX 焦点的形成，增加细胞凋亡，并降低照射（IR）和替莫唑胺（TMZ）治疗后的集落形成能力。此外，用 PGAM1 敲低细胞颅内植入的小鼠在接受 IR 和 TMZ 治疗后，生存时间显著延长。用两种激酶失活的 PGAM1 突变体 H186R 和 Y92F 表达外源，可抵消这些作用，表明 PGAM1 具有重要的非酶功能。我们的研究结果确定 PGAM1 是神经胶质瘤的一个潜在治疗靶点。
