Valvona Cara J, Fillmore Helen L
Cellular & Molecular Neuro-oncology Research Group, University of Portsmouth, School of Pharmacy & Biomedical Sciences, Portsmouth PO1 2DT, UK.
Brain Sci. 2018 Mar 30;8(4):56. doi: 10.3390/brainsci8040056.
Medulloblastoma is the most common malignant paediatric brain tumour and current therapies often leave patients with severe neurological disabilities. Four major molecular groups of medulloblastoma have been identified (Wnt, Shh, Group 3 and Group 4), which include additional, recently defined subgroups with different prognosis and genetic characteristics. Lactate dehydrogenase A (LDHA) is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly observed in cancers, associated with tumour progression and metastasis. Studies indicate MBs have a glycolytic phenotype; however, LDHA has not yet been explored as a therapeutic target for medulloblastoma. LDHA expression was examined in medulloblastoma subgroups and cell lines. The effects of LDHA inhibition by oxamate or LDHA siRNA on medulloblastoma cell line metabolism, migration and proliferation were examined. LDHA was significantly overexpressed in Group 3 and Wnt MBs compared to non-neoplastic cerebellum. Furthermore, we found that oxamate significantly attenuated glycolysis, proliferation and motility in medulloblastoma cell lines, but LDHA siRNA did not. We established that aerobic glycolysis is a potential therapeutic target for medulloblastoma, but broader LDH inhibition (LDHA, B, and C) may be more appropriate than LDHA inhibition alone.
髓母细胞瘤是最常见的儿童恶性脑肿瘤，目前的治疗方法常常使患者留下严重的神经功能残疾。已确定髓母细胞瘤的四个主要分子组（Wnt、Shh、3组和4组），其中包括最近定义的具有不同预后和遗传特征的其他亚组。乳酸脱氢酶A（LDHA）是有氧糖酵解途径中的关键酶，这是一种在癌症中常见的异常代谢途径，与肿瘤进展和转移相关。研究表明髓母细胞瘤具有糖酵解表型；然而，LDHA尚未作为髓母细胞瘤的治疗靶点进行探索。在髓母细胞瘤亚组和细胞系中检测了LDHA表达。研究了草氨酸或LDHA siRNA抑制LDHA对髓母细胞瘤细胞系代谢、迁移和增殖的影响。与非肿瘤性小脑相比，3组和Wnt髓母细胞瘤中LDHA显著过表达。此外，我们发现草氨酸显著减弱了髓母细胞瘤细胞系中的糖酵解、增殖和运动能力，但LDHA siRNA没有。我们确定有氧糖酵解是髓母细胞瘤的一个潜在治疗靶点，但更广泛的乳酸脱氢酶抑制（LDHA、B和C）可能比单独抑制LDHA更合适。
