Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China.
Cell Death Dis. 2018 Sep 24;9(10):988. doi: 10.1038/s41419-018-1015-x.
Plastic phenotype convention between glioma stem cells (GSCs) and non-stem tumor cells (NSTCs) significantly fuels glioblastoma heterogeneity that causes therapeutic failure. Recent progressions indicate that glucose metabolic reprogramming could drive cell fates. However, the metabolic pattern of GSCs and NSTCs and its association with tumor cell phenotypes remain largely unknown. Here we found that GSCs were more glycolytic than NSTCs, and voltage-dependent anion channel 2 (VDAC2), a mitochondrial membrane protein, was critical for metabolic switching between GSCs and NSTCs to affect their phenotypes. VDAC2 was highly expressed in NSTCs relative to GSCs and coupled a glycolytic rate-limiting enzyme platelet-type of phosphofructokinase (PFKP) on mitochondrion to inhibit PFKP-mediated glycolysis required for GSC maintenance. Disruption of VDAC2 induced dedifferentiation of NSTCs to acquire GSC features, including the enhanced self-renewal, preferential expression of GSC markers, and increased tumorigenicity. Inversely, enforced expression ofVDAC2 impaired the self-renewal and highly tumorigenic properties of GSCs. PFK inhibitor clotrimazole compromised the effect of VDAC2 disruption on glycolytic reprogramming and GSC phenotypic transition. Clinically, VDAC2 expression inversely correlated with glioma grades (Immunohistochemical staining scores of VDAC2 were 4.7 ± 2.8, 3.2 ± 1.9, and 1.9 ± 1.9 for grade II, grade III, and IV, respectively, p < 0.05 for all) and the patients with high expression of VDAC2 had longer overall survival than those with low expression of VDAC2 (p = 0.0008). In conclusion, we demonstrate that VDAC2 is a new glycolytic regulator controlling the phenotype transition between glioma stem cells and non-stem cells and may serves as a new prognostic indicator and a potential therapeutic target for glioma patients.
神经胶质瘤干细胞（GSCs）和非干细胞肿瘤细胞（NSTCs）之间的可塑性表型特征显著促进胶质母细胞瘤异质性，导致治疗失败。最近的研究进展表明，葡萄糖代谢重编程可能会驱动细胞命运。然而，GSCs 和 NSTCs 的代谢模式及其与肿瘤细胞表型的关联在很大程度上仍然未知。在这里，我们发现 GSCs 比 NSTCs 具有更高的糖酵解能力，而电压依赖性阴离子通道 2（VDAC2），一种线粒体膜蛋白，对于 GSCs 和 NSTCs 之间的代谢转换至关重要，从而影响它们的表型。VDAC2 在 NSTCs 中的表达水平明显高于 GSCs，并且与线粒体上的糖酵解限速酶血小板型磷酸果糖激酶（PFKP）偶联，以抑制 GSC 维持所需的 PFKP 介导的糖酵解。VDAC2 的破坏诱导 NSTCs 去分化获得 GSC 特征，包括增强的自我更新、GSC 标志物的优先表达以及增加的致瘤性。相反，强制表达 VDAC2 会损害 GSCs 的自我更新和高度致瘤特性。PFK 抑制剂克霉唑削弱了 VDAC2 破坏对糖酵解重编程和 GSC 表型转变的影响。临床上，VDAC2 的表达与胶质瘤分级呈负相关（VDAC2 的免疫组织化学染色评分分别为 4.7±2.8、3.2±1.9 和 1.9±1.9，对于 II 级、III 级和 IV 级，p<0.05），并且高表达 VDAC2 的患者的总生存期长于低表达 VDAC2 的患者（p=0.0008）。总之，我们证明 VDAC2 是一种新的糖酵解调节剂，可控制神经胶质瘤干细胞和非干细胞之间的表型转变，可能作为神经胶质瘤患者的新预后指标和潜在治疗靶点。
