PDF(Pubmed)
Abstract：
The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy.
摘要：
液泡质子易位ATPase（V-ATPase）是维持正常细胞内pH值的跨膜多蛋白复合物。在肿瘤比赛中，它的作用至关重要，因为致癌作用的代谢主要基于厌氧糖酵解反应。此外，肿瘤细胞使用V-ATPase将化疗药物挤出到细胞外区室作为耐药机制。在胶质母细胞瘤（GBM）中，最恶性和无法治愈的原发性脑肿瘤，这个泵的表达式被上调，使其成为新的可能的治疗靶点。在这项工作中,与替莫唑胺一起评估了患者来源的神经胶质瘤干细胞（GSC）系中巴弗洛霉素A1诱导的V-ATPase抑制作用，针对GBM的一线治疗。与以前公布的数据相比，建议的治疗方法未能克服对标准治疗的耐药性.此外,我们的数据显示，纳摩尔剂量的巴弗洛霉素A1导致自噬过程和细胞坏死的阻断，使药物在更复杂的模型中无法使用。然而，巴弗洛霉素A1后V-ATP酶的表达增加表明质子泵在GBM茎组分中的关键作用，鼓励寻找新的策略来限制其活性，以规避对常规治疗的抵抗。
