Glutaminase 2 as a therapeutic target in glioblastoma

IF 9.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochimica et biophysica acta. Reviews on cancer Pub Date : 2024-09-16 DOI:10.1016/j.bbcan.2024.189182
Rithvik K. Veeramachaneni, Robert K. Suter, Emma Rowland, Anna Jermakowicz, Nagi G. Ayad
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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.

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作为胶质母细胞瘤治疗靶点的谷氨酰胺酶 2。
胶质母细胞瘤(GBM)是最常见的恶性原发性成人脑肿瘤。尽管标准治疗包括手术切除、替莫唑胺(TMZ)治疗和放射治疗,但 GBM 患者的预后仍然很差,五年生存率仅为 5%。经过治疗后,中位生存期为 14 个月,这表明迫切需要更有效的新疗法。谷氨酰胺溶解是细胞将谷氨酰胺转化为 ATP 的代谢途径,对 GBM 细胞的存活至关重要,也是治疗的潜在靶点。谷氨酰胺通过谷氨酰胺分解补充三羧酸(TCA)循环中间产物。谷氨酰胺分解的第一步,即谷氨酰胺的脱氨,可由谷氨酰胺酶 1 (GLS) 或谷氨酰胺酶 2 (GLS2) 完成。然而,人们越来越清楚地认识到,这两种酶在 GBM 中具有相反的功能;GLS 诱导谷氨酰胺的脱氨,从而以致癌的方式发挥作用,而 GLS2 则具有非酶抑制肿瘤的功能,在 GBM 中受到抑制。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 中的对立作用。此外,我们还详细讨论了新发现的 GLS2 在 GBM 中的非酶功能。最后,我们考虑了通过了解 GLS 和 GLS2 在 GBM 中的对立作用而产生的治疗方法。
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来源期刊
Biochimica et biophysica acta. Reviews on cancer
Biochimica et biophysica acta. Reviews on cancer 医学-生化与分子生物学
CiteScore
17.20
自引率
0.00%
发文量
138
审稿时长
33 days
期刊介绍: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer encompasses the entirety of cancer biology and biochemistry, emphasizing oncogenes and tumor suppressor genes, growth-related cell cycle control signaling, carcinogenesis mechanisms, cell transformation, immunologic control mechanisms, genetics of human (mammalian) cancer, control of cell proliferation, genetic and molecular control of organismic development, rational anti-tumor drug design. It publishes mini-reviews and full reviews.
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