The Institute of Cell Metabolism and Diseases, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China; Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China.
Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China.
Mol Cell. 2021 Jun 3;81(11):2303-2316.e8. doi: 10.1016/j.molcel.2021.04.002. Epub 2021 May 14.
Glutaminase regulates glutaminolysis to promote cancer cell proliferation. However, the mechanism underlying glutaminase activity regulation is largely unknown. Here, we demonstrate that kidney-type glutaminase (GLS) is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens with correspondingly upregulated glutamine dependence for PDAC cell proliferation. Upon oxidative stress, the succinyl-coenzyme A (CoA) synthetase ADP-forming subunit β (SUCLA2) phosphorylated by p38 mitogen-activated protein kinase (MAPK) at S79 dissociates from GLS, resulting in enhanced GLS K311 succinylation, oligomerization, and activity. Activated GLS increases glutaminolysis and the production of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, thereby counteracting oxidative stress and promoting tumor cell survival and tumor growth in mice. In addition, the levels of SUCLA2 pS79 and GLS K311 succinylation, which were mutually correlated, were positively associated with advanced stages of PDAC and poor prognosis for patients. Our findings reveal critical regulation of GLS by SUCLA2-coupled GLS succinylation regulation and underscore the regulatory role of metabolites in glutaminolysis and PDAC development.
谷氨酰胺酶通过调节谷氨酰胺分解代谢促进癌细胞增殖。然而，谷氨酰胺酶活性调节的机制在很大程度上尚不清楚。在这里，我们证明肾型谷氨酰胺酶（GLS）在人胰腺导管腺癌（PDAC）标本中高度表达，相应地增加了 PDAC 细胞增殖对谷氨酰胺的依赖性。在氧化应激下，p38 丝裂原活化蛋白激酶（MAPK）磷酸化 SUCLA2 的 ADP 形成亚基β（SUCLA2）在 S79 处磷酸化，与 GLS 分离，导致 GLS K311 琥珀酰化、寡聚化和活性增强。激活的 GLS 增加了谷氨酰胺分解代谢以及烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和谷胱甘肽的产生，从而抵消了氧化应激，促进了小鼠肿瘤细胞的存活和肿瘤生长。此外，SUCLA2 pS79 和 GLS K311 琥珀酰化的水平相互关联，与 PDAC 的晚期阶段和患者的预后不良呈正相关。我们的研究结果揭示了 SUCLA2 偶联的 GLS 琥珀酰化调节对 GLS 的关键调节作用，并强调了代谢物在谷氨酰胺分解代谢和 PDAC 发生发展中的调节作用。
