Lactate Transporters and pH Regulation: Potential Therapeutic Targets in Glioblastomas
Lactate Transporters and pH Regulation: Potential Therapeutic Targets in Glioblastomas
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DOI：
10.2174/1568009616666151222150543
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发表时间：
2016-01-01
影响因子：
3
通讯作者：
Baltazar, Fatima
中科院分区：
文献类型：
--
作者：
Miranda-Goncalves, Vera;Reis, Rui M.;Baltazar, Fatima
尽管治疗取得了进展，胶质母细胞瘤（GBM）仍然是最普遍和最致命的脑肿瘤。因此，当务之急是确定新的和有效的治疗方法，可以改善这些患者的生活。众所周知，肿瘤细胞，如胶质母细胞瘤，存在代谢重编程，称为“瓦尔堡效应”，现在被认为是癌症的标志。这种机制与肿瘤细胞对糖酵解代谢的高度依赖性有关，以维持能量需求和大分子合成，导致产生大量的乳酸和碳酸。这些代谢产物诱导微环境酸化，由于上调几种蛋白质，如单羧酸转运蛋白（MCT）和碳酸酐酶（CA），以维持糖酵解表型和细胞内生理pH。糖酵解代谢和酸性微环境对标准治疗的获得性耐药的依赖性已成为胶质母细胞瘤治疗反应的研究热点。在这篇综述中，我们打算强调乳酸转运蛋白和其他pH调节剂在GBM中的重要性的证据，这些转运蛋白和pH调节剂在GBM中经常过表达，并与肿瘤的侵袭性相关。此外，我们将描述如何针对这些蛋白质可以构成新的治疗策略，以克服胶质瘤耐药治疗。
Despite advances in therapy, glioblastoma (GBM) is still the most prevalent and lethal brain tumor. Thus, it is imperative to identify new and effective therapies that could improve the lifetime of these patients. It is known that tumor cells, such as glioblastomas present metabolic reprogramming, named "Warburg effect", recognized nowadays as a hallmark of cancer. This mechanism is associated with a high dependence of tumor cells on the glycolytic metabolism to sustain energy demands and macromolecule synthesis, leading to production of high amounts of lactic and carbonic acids. These metabolic products induce microenvironment acidification, due to up-regulation of several proteins, such as monocarboxylate transporters (MCTs) and carbonic anhydrases (CAs), to maintain the glycolytic phenotype and the intracellular physiological pH. The dependence on glycolytic metabolism and acidic microenvironment on the acquired resistance to standard therapy has been a research focus in glioblastoma therapy response. In this review, we intend to highlight evidence for the importance of lactate transporters and other pH regulators in GBMs, which are frequently overexpressed in GBMs and associated with tumor aggressiveness. Moreover, we will describe how targeting these proteins could constitute new therapeutic strategies to overcome glioma resistance to therapy.