谷氨酰胺酶2作为胶质母细胞瘤的治疗靶点
Glutaminase 2 as a therapeutic target in glioblastoma
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影响因子:8.3
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
DOI:
10.1016/j.bbcan.2024.189182
摘要
胶质母细胞瘤（GBM）是成人最常见的恶性原发性脑肿瘤。尽管采用手术切除、替莫唑胺（TMZ）治疗和放疗的标准治疗方案，但GBM患者的预后仍然较差，五年生存率仅为5%。治疗中位生存时间为14个月，显示出亟需开发新的更有效的治疗方法。谷氨酰胺酶解作用（谷氨酰胺向ATP转化的代谢途径）对于GBM细胞的存活至关重要，是潜在的治疗靶点。谷氨酰胺通过谷氨酰胺酶解作用补充三羧酸循环（TCA）中间体。谷氨酰胺酶解的第一步，谷氨酰胺的去氨基反应，可以由谷氨酰胺酶1（GLS）或谷氨酰胺酶2（GLS2）催化。然而，越来越多的证据表明，这些酶在GBM中具有相反的功能：GLS促使谷氨酰胺的去氨基，具有促癌作用，而GLS2则具有非酶促的肿瘤抑制功能，在GBM中受到抑制。本文回顾了谷氨酰胺酶解作用及GLS与GLS2在GBM中的对立作用的关键角色。此外，我们还详细讨论了GLS2新发现的非酶促功能及其在GBM中的潜在靶向策略。最后，本文探讨了基于对GLS与GLS2相反作用的理解而提出的治疗策略。
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.