Skaripa-Koukelli Irini, Hauton David, Walsby-Tickle John, Thomas Eloïse, Owen Joshua, Lakshminarayanan Abirami, Able Sarah, McCullagh James, Carlisle Robert C, Vallis Katherine A
Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ, UK.
Cancer Metab. 2021 Oct 14;9(1):37. doi: 10.1186/s40170-021-00273-6.
BACKGROUND: Triple negative breast cancer (TNBC) poses a serious clinical challenge as it is an aggressive form of the disease that lacks estrogen receptor, progesterone receptor, and ERBB2 (formerly HER2) gene amplification, which limits the treatment options. The Warburg phenotype of upregulated glycolysis in the presence of oxygen has been shown to be prevalent in TNBC. Elevated glycolysis satisfies the energy requirements of cancer cells, contributes to resistance to treatment by maintaining redox homeostasis and generating nucleotide precursors required for cell proliferation and DNA repair. Expression of the monocarboxylate transporter 1 (MCT1), which is responsible for the bidirectional transport of lactate, correlates with an aggressive phenotype and poor outcome in several cancer types, including breast cancer. In this study, 3-bromopyruvate (3BP), a lactate/pyruvate analog, was used to selectively target TNBC cells that express MCT1. METHODS: The cytotoxicity of 3BP was tested in MTT assays using human TNBC cell lines: BT20 (MCT1/MCT4), MDA-MB-23 (MCT1/MCT4), and BT20 in which MCT1 was knocked down (siMCT1-BT20). The metabolite profile of 3BP-treated and 3BP-untreated cells was investigated using LC-MS/MS. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of BT20 and MDA-MB-231 cells treated with 3BP were measured using a Seahorse XF96 extracellular flux analyzer. The impact of ionizing radiation on cell survival, alone or in combination with 3BP pre-treatment, was evaluated using clonogenic assays. RESULTS: Metabolomic analyses showed that 3BP causes inhibition of glycolysis, disturbance of redox homeostasis, decreased nucleotide synthesis, and was accompanied by a reduction in medium acidification. In addition, 3BP potentiated the cytotoxic effect of ionizing radiation, a treatment that is frequently used in the management of TNBC. CONCLUSIONS: Overall, MCT1-mediated metabolic perturbation in combination with radiotherapy is shown to be a promising strategy for the treatment of glycolytic tumors such as TNBC, overcoming the selectivity challenges of targeting glycolysis with glucose analogs.
背景：三阴性乳腺癌（TNBC）是一种侵袭性疾病，缺乏雌激素受体、孕激素受体以及ERBB2（原HER2）基因扩增，这限制了治疗选择，因此对临床治疗构成严峻挑战。在有氧情况下糖酵解上调的瓦博格表型在TNBC中很常见。糖酵解增强满足了癌细胞的能量需求，通过维持氧化还原稳态和生成细胞增殖及DNA修复所需的核苷酸前体，有助于产生治疗抗性。负责乳酸双向转运的单羧酸转运蛋白1（MCT1）的表达与包括乳腺癌在内的几种癌症类型的侵袭性表型和不良预后相关。在本研究中，乳酸/丙酮酸类似物3-溴丙酮酸（3BP）被用于选择性靶向表达MCT1的TNBC细胞。 方法：使用人TNBC细胞系BT20（MCT1/MCT4）、MDA-MB-23（MCT1/MCT4）以及MCT1被敲低的BT20（siMCT1-BT20），通过MTT试验检测3BP的细胞毒性。使用液相色谱-串联质谱法（LC-MS/MS）研究3BP处理和未处理细胞的代谢物谱。使用海马XF96细胞外通量分析仪测量3BP处理的BT20和MDA-MB-231细胞的细胞外酸化率（ECAR）和耗氧率（OCR）。使用克隆形成试验评估电离辐射单独或与3BP预处理联合对细胞存活的影响。 结果：代谢组学分析表明，3BP导致糖酵解受到抑制、氧化还原稳态紊乱、核苷酸合成减少，并伴随着培养基酸化程度降低。此外，3BP增强了电离辐射的细胞毒性作用，电离辐射是TNBC治疗中常用的一种治疗方法。 结论：总体而言，MCT1介导的代谢扰动与放射治疗相结合被证明是治疗TNBC等糖酵解肿瘤的一种有前景的策略，克服了使用葡萄糖类似物靶向糖酵解的选择性挑战。
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