背景:聚(形态)核巨细胞(PGCs)的多药耐药性决定了它们在癌症生态系统中的细胞保护和生成潜力。然而,PGCs参与多形性胶质母细胞瘤(GBM)适应化疗方案的潜在机制在很大程度上仍不清楚.特别是,从多柔比星(DOX)诱导的应激中恢复GBM方面,尚未考虑PGCs的代谢重编程。
方法:应用长期蛋白质组学和代谢细胞谱分析来追踪体外接受脉冲DOX处理的GBM群体的表型动力学,特别关注PGC的形成及其代谢背景。代谢重编程之间的联系,评估PGCs的耐药性和药物保留能力,以及它们对从DOX诱导的应激中恢复GBM的意义。
结果:脉冲DOX治疗触发了PGCs的瞬时形成,随后出现小的扩增细胞(SEC)簇。PGCs的发育伴随着其代谢蛋白质组的动员,瞬时诱导氧化磷酸化(OXPHOS),和NADH的差异细胞内积累,NADPH,和ATP。PGC形成的代谢背景通过GSK-3β化学抑制后从DOX诱导的应激中GBM恢复的衰减来证实,OXPHOS,和磷酸戊糖途径。同时,观察到PGCs中活性氧(ROS)清除系统的动员和NADPH依赖性ROS产生系统的微调。这些过程伴随着ABCB1和ABCG2转运蛋白的核周动员以及核周PGC隔室中的DOX保留。
结论:这些数据证明了GBM从DOX诱导的应激中恢复的合作模式以及PGCs代谢重编程在该过程中的关键作用。代谢重编程增强了自我防御系统的效率,并增加了PGCs的DOX保留能力,潜在地降低SECs附近的DOX生物利用度。因此,PGC代谢的调节被强调为胶质母细胞瘤治疗干预的潜在目标。
BACKGROUND: Multi-drug resistance of poly(morpho)nuclear giant cells (PGCs) determines their cytoprotective and generative potential in cancer ecosystems. However, mechanisms underlying the involvement of PGCs in glioblastoma multiforme (GBM) adaptation to chemotherapeutic regimes remain largely obscure. In particular, metabolic reprogramming of PGCs has not yet been considered in terms of GBM recovery from doxorubicin (DOX)-induced stress.
METHODS: Long-term proteomic and metabolic cell profiling was applied to trace the phenotypic dynamics of GBM populations subjected to pulse DOX treatment in vitro, with a particular focus on PGC formation and its metabolic background. The links between metabolic reprogramming, drug resistance and drug retention capacity of PGCs were assessed, along with their significance for GBM recovery from DOX-induced stress.
RESULTS: Pulse DOX treatment triggered the transient formation of PGCs, followed by the appearance of small expanding cell (SEC) clusters. Development of PGCs was accompanied by the mobilization of their metabolic proteome, transient induction of oxidative phosphorylation (OXPHOS), and differential intracellular accumulation of NADH, NADPH, and ATP. The metabolic background of PGC formation was confirmed by the attenuation of GBM recovery from DOX-induced stress following the chemical inhibition of GSK-3β, OXPHOS, and the pentose phosphate pathway. Concurrently, the mobilization of reactive oxygen species (ROS) scavenging systems and fine-tuning of NADPH-dependent ROS production systems in PGCs was observed. These processes were accompanied by perinuclear mobilization of ABCB1 and ABCG2 transporters and DOX retention in the perinuclear PGC compartments.
CONCLUSIONS: These data demonstrate the cooperative pattern of GBM recovery from DOX-induced stress and the crucial role of metabolic reprogramming of PGCs in this process. Metabolic reprogramming enhances the efficiency of self-defense systems and increases the DOX retention capacity of PGCs, potentially reducing DOX bioavailability in the proximity of SECs. Consequently, the modulation of PGC metabolism is highlighted as a potential target for intervention in glioblastoma treatment.