Abstract
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.
Highlights
Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor[1,2]
Blocking glycolysis with 2deoxy-D-glucose (2-DG), a widely used glycolysis inhibitor, markedly reduced ATP generation in glioma stem cells (GSCs) but slightly reduced ATP generation in non-stem tumor cells (NSTCs) (Fig. 1b), suggesting that GSCs are more relied on glycolysis, whereas NSTCs may largely depend on oxidative phosphorylation (OxPhos), for glucose metabolism
These results indicate that GSCs are more relied on glycolysis than NSTCs for the maintenance of cancer stem cells (CSCs) features
Summary
Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor[1,2]. Despite aggressive surgical resection, chemotherapy, and radiotherapy are performed, patients with GBMs still have dismal prognosis, with a Recent studies have demonstrated that GSCs are highly adaptive to various crucial conditions, including nutrient-restricted condition, hypoxia, or chemo-agent exposure[8,9,10], and actively interact with the Official journal of the Cell Death Differentiation AssociationZhou et al Cell Death and Disease (2018)9:988 microenvironmental factors to evade antitumor immune responses, promote tumor angiogenesis and tumor invasion[11,12,13], significantly contribute to tumor recurrence and the poor outcome of GBM patients[14,15]. Chemotherapy, and radiotherapy are performed, patients with GBMs still have dismal prognosis, with a Recent studies have demonstrated that GSCs are highly adaptive to various crucial conditions, including nutrient-restricted condition, hypoxia, or chemo-agent exposure[8,9,10], and actively interact with the Official journal of the Cell Death Differentiation Association. One major challenge for anti-GSC strategy is that both GSCs and its counterparts non-stem tumor cells (NSTCs) are plastic and capable of undergoing phenotypic transition. Convincing evidence has demonstrated that upon appropriate stimuli GSCs are capable to differentiate into NSTCs to sustain tumor growth[16]. Blocking the phenotypic transition between GSCs and NSTCs is of great translational significance to improve the efficacy of GSC-targeting therapy and to benefit GBM patients. The intrinsic driving force that determines the plasticity of GSCs and NSTCs is still largely unknown
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