Departamento de Bioquímica , Instituto Nacional de Cardiología , 14080 Tlalpan , CDMX , Mexico.
Laboratorio de Medicina Traslacional , Instituto Nacional de Cancerología , 14080 Tlalpan , CDMX , Mexico.
Mol Pharm. 2018 Jun 4;15(6):2151-2164. doi: 10.1021/acs.molpharmaceut.8b00015. Epub 2018 May 23.
To establish alternative targeted therapies against triple negative (TN) breast cancer, the energy metabolism and the sensitivity of cell growth, migration, and invasiveness toward metabolic, canonical, and NSAID inhibitors were analyzed in MDA-MB-231 and MDA-MB-468, two TN metastatic breast cancer cell lines, under both normoxia (21% O) and hypoxia (0.1% O). For comparative purposes, the analysis was also carried out in the less-metastatic breast MCF-7 cancer cells. Under normoxia, oxidative phosphorylation (OxPhos) was significantly higher (2-times) in MDA-MB-468 than in MDA-MB-231 and MCF-7, whereas their glycolytic fluxes and OxPhos and glycolytic protein contents were all similar. TN cancer cell lines mainly depended on OxPhos (62-75%), whereas MCF-7 cells equally depended on both pathways for ATP supply. Hypoxia for 24 h promoted a significant increase (>20 times) in the glycolytic transcriptional master factor HIF1-α in its target proteins GLUT-1, HKI and II, and LDH-A (2-4 times) as well as in the glycolytic flux (1.3-2 times) vs normoxia in MDA-MB-468, MDA-MB-231, and MCF-7. On the contrary, hypoxia decreased (15-60%) the contents of COXIV, 2OGDH, ND1, and ATP synthase as well as the OxPhos flux (50-75%), correlating with a high mitophagy level in the three cell lines. Under hypoxia, the three cancer cell lines mainly depended on glycolysis (70-80%). Anti-mitochondrial drugs (oligomycin, casiopeina II-gly, and methoxy-TEA) and celecoxib, at doses used to block OxPhos, significantly decreased TN cancer cell proliferation (IC = 2-20 μM), migration capacity (10-90%), and invasiveness (25-65%). The present data support the use of mitochondrially targeted inhibitors for the treatment of TN breast carcinoma.
为了建立针对三阴性（TN）乳腺癌的替代靶向治疗方法，我们分析了 MDA-MB-231 和 MDA-MB-468 这两种 TN 转移性乳腺癌细胞系在常氧（21% O）和缺氧（0.1% O）条件下的能量代谢和细胞生长、迁移和侵袭对代谢、经典和非甾体抗炎药抑制剂的敏感性。为了进行比较，我们还在转移性较低的乳腺癌 MCF-7 细胞中进行了分析。在常氧条件下，MDA-MB-468 的氧化磷酸化（OxPhos）明显高于 MDA-MB-231 和 MCF-7（2 倍），而它们的糖酵解通量和 OxPhos 及糖酵解蛋白含量均相似。TN 癌细胞系主要依赖 OxPhos（62-75%），而 MCF-7 细胞则同等依赖两种途径提供 ATP。缺氧 24 小时后，在 MDA-MB-468、MDA-MB-231 和 MCF-7 中，糖酵解转录主因子 HIF1-α及其靶蛋白 GLUT-1、HKI 和 II 以及 LDH-A（2-4 倍）的表达均显著增加（>20 倍），糖酵解通量（1.3-2 倍）也显著增加。相反，缺氧（15-60%）降低了 COXIV、2OGDH、ND1 和 ATP 合酶的含量以及 OxPhos 通量（50-75%），与三种细胞系中的高线粒体自噬水平相关。在缺氧条件下，三种癌细胞系主要依赖糖酵解（70-80%）。线粒体靶向药物（寡霉素、卡西奥皮纳 II-gly 和甲氧基-TEA）和塞来昔布（用于阻断 OxPhos 的剂量）显著降低了 TN 癌细胞的增殖（IC = 2-20 μM）、迁移能力（10-90%）和侵袭能力（25-65%）。这些数据支持使用靶向线粒体的抑制剂治疗 TN 乳腺癌。
