Udutha Suresh, Taglang Céline, Batsios Georgios, Gillespie Anne Marie, Tran Meryssa, Hoeve Johanna Ten, Graeber Thomas G, Viswanath Pavithra
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, Los Angeles, CA, USA; UCLA Metabolomics Center, Los Angeles, CA, USA.
Cell Rep. 2025 May 27;44(5):115596. doi: 10.1016/j.celrep.2025.115596. Epub 2025 Apr 19.
Understanding the mechanisms by which oncogenic events alter metabolism will help identify metabolic weaknesses that can be targeted for therapy. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance in most cancers. Here, we show that TERT acts via the transcription factor forkhead box O1 (FOXO1) to upregulate glutamate-cysteine ligase (GCLC), the rate-limiting enzyme for de novo biosynthesis of glutathione (GSH, reduced) in multiple cancer models, including glioblastoma (GBM). Genetic ablation of GCLC or pharmacological inhibition using buthionine sulfoximine (BSO) reduces GSH synthesis from [U-C]-glutamine in GBMs. However, GCLC inhibition drives de novo pyrimidine nucleotide biosynthesis by upregulating the glutamine-utilizing enzymes glutaminase (GLS) and carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotatase (CAD) in an MYC-driven manner. Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs.
了解致癌事件改变代谢的机制将有助于识别可作为治疗靶点的代谢弱点。端粒酶逆转录酶（TERT）在大多数癌症中对端粒维持至关重要。在此，我们表明，在包括胶质母细胞瘤（GBM）在内的多种癌症模型中，TERT通过转录因子叉头框O1（FOXO1）发挥作用，上调谷氨酸-半胱氨酸连接酶（GCLC）——谷胱甘肽（GSH，还原型）从头生物合成的限速酶。GCLC的基因敲除或使用丁硫氨酸亚砜胺（BSO）的药理学抑制可降低GBM中[U-C]-谷氨酰胺的GSH合成。然而，GCLC抑制通过以MYC驱动的方式上调利用谷氨酰胺的酶谷氨酰胺酶（GLS）和氨甲酰磷酸合成酶2、天冬氨酸转氨甲酰酶和二氢乳清酸酶（CAD）来驱动嘧啶核苷酸的从头生物合成。将BSO与谷氨酰胺拮抗剂JHU-083联合使用在体外和体内具有合成致死性，并显著延长了携带颅内GBM异种移植物的小鼠的生存期。总体而言，我们的研究推进了我们对GBM中癌基因诱导的代谢脆弱性的理解。
Zotero 插件
