Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany.
Blood Adv. 2023 Dec 26;7(24):7433-7444. doi: 10.1182/bloodadvances.2023010964.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, but first-line immunochemotherapy fails to produce a durable response in about one-third of the patients. Because tumor cells often reprogram their metabolism, we investigated the importance of glutaminolysis, a pathway converting glutamine to generate energy and various metabolites, for the growth of DLBCL cells. Glutaminase-1 (GLS1) expression was robustly detected in DLBCL biopsy samples and cell lines. Both pharmacological inhibition and genetic knockdown of GLS1 induced cell death in DLBCL cells regardless of their subtype classification, whereas primary B cells remained unaffected. Interestingly, GLS1 inhibition resulted not only in reduced levels of intermediates of the tricarboxylic acid cycle but also in a strong mitochondrial accumulation of reactive oxygen species. Supplementation of DLBCL cells with α-ketoglutarate or with the antioxidant α-tocopherol mitigated oxidative stress and abrogated cell death upon GLS1 inhibition, indicating an essential role of glutaminolysis in the protection from oxidative stress. Furthermore, the combination of the GLS1 inhibitor CB-839 with the therapeutic BCL2 inhibitor ABT-199 not only induced massive reactive oxygen species (ROS) production but also exhibited highly synergistic cytotoxicity, suggesting that simultaneous targeting of GLS1 and BCL2 could represent a novel therapeutic strategy for patients with DLBCL.
弥漫性大 B 细胞淋巴瘤（DLBCL）是成人中最常见的淋巴瘤，但大约三分之一的患者对一线免疫化疗没有持久的反应。由于肿瘤细胞经常重新编程其代谢，我们研究了谷氨酰胺分解代谢的重要性，谷氨酰胺分解代谢是一种将谷氨酰胺转化为产生能量和各种代谢物的途径，对 DLBCL 细胞的生长很重要。在 DLBCL 活检样本和细胞系中强烈检测到谷氨酰胺酶 1（GLS1）的表达。无论其亚型分类如何，GLS1 的药理学抑制和基因敲低均可诱导 DLBCL 细胞死亡，而原代 B 细胞不受影响。有趣的是，GLS1 抑制不仅导致三羧酸循环中间产物水平降低，而且还导致活性氧在线粒体中的大量积累。向 DLBCL 细胞补充α-酮戊二酸或抗氧化剂α-生育酚可减轻氧化应激并消除 GLS1 抑制后的细胞死亡，表明谷氨酰胺分解代谢在保护免受氧化应激方面起着重要作用。此外，GLS1 抑制剂 CB-839 与治疗性 BCL2 抑制剂 ABT-199 的联合不仅诱导大量活性氧（ROS）的产生，而且表现出高度协同的细胞毒性，表明同时靶向 GLS1 和 BCL2 可能代表 DLBCL 患者的一种新的治疗策略。
