谷氨酰胺酶2作为胶质母细胞瘤的治疗靶标
Glutaminase 2 as a therapeutic target in glioblastoma
影响因子:8.30000
分区:医学2区 Top / 生化与分子生物学2区 生物物理2区 肿瘤学2区
发表日期:2024 Nov
作者:
Rithvik K Veeramachaneni, Robert K Suter, Emma Rowland, Anna Jermakowicz, Nagi G Ayad
摘要
胶质母细胞瘤（GBM）是最常见的恶性原发性成人脑肿瘤。尽管护理标准的治疗方法包括手术切除，替莫唑胺（TMZ）治疗和放射疗法，但GBM患者的预后仍然很差，五年生存率为5％。通过治疗，中位生存时间为14个月，这表明需要新的，更有效的疗法。谷氨酰胺溶解是细胞可以将谷氨酰胺转化为ATP的代谢途径，对于GBM细胞的存活至关重要，代表了假定的治疗靶标。谷氨酰胺通过谷氨酰胺溶解补充三羧酸（TCA）循环中间。谷氨酰胺溶解的第一步，谷氨酰胺的脱氨酸，可以通过谷氨酰胺酶1（GLS）或谷氨酰胺酶2（GLS2）进行。但是，越来越清楚的是，这些酶在GBM中具有相反的功能。 GLS诱导谷氨酰胺的脱氨酸，从而以致癌方式作用，而GLS2具有非酶，抑制肿瘤的功能，在GBM中被抑制。在这篇综述中，我们探讨了谷氨酰胺溶解的重要作用以及GLS和GLS2在GBM中的相对作用。此外，我们对GLS2新发现的非酶函数进行了详细讨论，该功能可以针对GBM。我们通过考虑对GLS和GLS2在GBM中相反的角色的理解中出现的治疗方法来得出结论。
Abstract
Glioblastoma (GBM) is the most common malignant primary adult brain tumor. Despite standard-of-care treatment, which consists of surgical resection, temozolomide (TMZ) treatment, and radiotherapy, the prognosis for GBM patients remains poor with a five-year survival rate of 5 %. With treatment, the median survival time is 14 months, suggesting the dire need for new, more effective therapies. Glutaminolysis, the metabolic pathway by which cells can convert glutamine to ATP, is essential for the survival of GBM cells and represents a putative target for treatment. Glutamine replenishes tricarboxylic acid (TCA) cycle intermediates through glutaminolysis. The first step of glutaminolysis, the deamination of glutamine, can be carried out by either glutaminase 1 (GLS) or glutaminase 2 (GLS2). However, it is becoming increasingly clear that these enzymes have opposing functions in GBM; GLS induces deamination of glutamine, thereby acting in an oncogenic fashion, while GLS2 has non-enzymatic, tumor-suppressive functions that are repressed in GBM. In this review, we explore the important role of glutaminolysis and the opposing roles of GLS and GLS2 in GBM. Further, we provide a detailed discussion of GLS2's newly discovered non-enzymatic functions that can be targeted in GBM. We conclude by considering therapeutic approaches that have emerged from the understanding of GLS and GLS2's opposing roles in GBM.