Mitochondrial bioenergetic adaptations of breast cancer cells to aglycemia and hypoxia
Mitochondrial bioenergetic adaptations of breast cancer cells to aglycemia and hypoxia
复制标题
DOI：
10.1007/s10863-009-9267-x
复制
发表时间：
2010-02-01
影响因子：
3
通讯作者：
Rossignol, Rodrigue
中科院分区：
文献类型：
--
作者：
Smolkova, Katarina;Bellance, Nadege;Rossignol, Rodrigue
乳腺癌细胞可以在营养缺乏的恶劣条件下存活和增殖，包括有限的氧气和葡萄糖供应。我们假设，这种环境会触发线粒体的新陈代谢适应，从而促进肿瘤的进展。在这里，我们在体外模拟血糖和缺氧，并比较了来源于乳腺组织的人乳腺癌(HTB-126)和非乳腺癌(HTB-125)细胞的线粒体和细胞生物能量适应能力。使用高分辨率呼吸测量法和蛋白质印迹分析，我们证明，4天的葡萄糖剥夺使氧化磷酸化增加了五倍，增加了线粒体网络的铺展而不改变其形状，并降低了癌细胞对氧的表观亲和力(C(50)增加)，而在对照细胞中保持不变。在适应后，底物控制比率也保持不变。我们还观察到了克拉布特里效应，特别是在HTB-126细胞中。同样，持续低氧(6天内含1%氧气)可改善生长在葡萄糖或无葡萄糖(分别为+32%和+38%)中的非癌细胞的呼吸。相反，在这些限制氧气或缺氧和葡萄糖联合剥夺6天的条件下，癌细胞的常规呼吸明显减少(葡萄糖培养基中为-36%，无糖培养基中为-24%)。这些数据表明，癌细胞在使其生物能量适应微环境条件时的行为与正常细胞不同。在优化乳腺癌治疗策略时，乳腺癌细胞和非癌细胞之间在缺氧和血糖耐受性方面的差异可能是重要的。
Breast cancer cells can survive and proliferate under harsh conditions of nutrient deprivation, including limited oxygen and glucose availability. We hypothesized that such environments trigger metabolic adaptations of mitochondria, which promote tumor progression. Here, we mimicked aglycemia and hypoxia in vitro and compared the mitochondrial and cellular bioenergetic adaptations of human breast cancer (HTB-126) and non-cancer (HTB-125) cells that originate from breast tissue. Using high-resolution respirometry and western blot analyses, we demonstrated that 4 days of glucose deprivation elevated oxidative phosphorylation five-fold, increased the spread of the mitochondrial network without changing its shape, and decreased the apparent affinity of oxygen in cancer cells (increase in C (50) ), whereas it remained unchanged in control cells. The substrate control ratios also remained constant following adaptation. We also observed the Crabtree effect, specifically in HTB-126 cells. Likewise, sustained hypoxia (1% oxygen during 6 days) improved cell respiration in non-cancer cells grown in glucose or glucose-deprived medium (+ 32% and +38%, respectively). Conversely, under these conditions of limited oxygen or a combination of oxygen and glucose deprivation for 6 days, routine respiration was strongly reduced in cancer cells (-36% in glucose medium, -24% in glucose-deprived medium). The data demonstrate that cancer cells behave differently than normal cells when adapting their bioenergetics to microenvironmental conditions. The differences in hypoxia and aglycemia tolerance between breast cancer cells and non-cancer cells may be important when optimizing strategies for the treatment of breast cancer.