Central role of lactic acidosis in cancer cell resistance to glucose deprivation-induced cell death
Central role of lactic acidosis in cancer cell resistance to glucose deprivation-induced cell death
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乳酸性酸中毒在癌细胞抵抗葡萄糖剥夺诱导的细胞死亡中的核心作用
DOI：
10.1002/path.3978
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发表时间：
2012-06-01
影响因子：
7.3
通讯作者：
Hu, Xun
中科院分区：
文献类型：
--
作者：
Wu, Hao;Ding, Zonghui;Hu, Xun
实体瘤依赖于葡萄糖，但由于血管生成不良，通常缺乏葡萄糖。然而，通常情况下，癌细胞在葡萄糖缺乏的情况下比正常细胞更能存活。因此，使癌细胞对葡萄糖耗竭敏感可能为癌症干预提供一种有效的策略。我们认为，乳酸酸中毒是一种肿瘤微环境因素，可能允许癌细胞对葡萄糖剥夺诱导的死亡产生抵抗力，而乳酸酸中毒的破坏可能会恢复癌细胞对葡萄糖耗竭的敏感性。乳酸血症、乳酸血症或酸中毒是通过在培养基中加入纯乳酸、乳酸钠或盐酸而产生的。在葡萄糖剥夺和乳酸酸中毒条件下，对存活的癌细胞的细胞死亡、细胞周期、自噬、细胞凋亡和基因表达谱进行了测定。与之形成鲜明对比的是，在无乳酸酸中毒的缺糖条件下，4T1癌细胞中90%的细胞在一天内死亡；与之形成鲜明对比的是，在乳酸酸中毒条件下，90%的4T1细胞在10天内死亡，甚至在葡萄糖耗尽65天后也能发现活细胞。葡萄糖恢复后，存活的细胞恢复了增殖。乳酸酸中毒还显著延长了其他癌细胞在葡萄糖剥夺下的存活时间。G_1/G_0期停滞、自噬诱导和细胞凋亡抑制与乳酸酸中毒介导的葡萄糖剥夺抵抗密切相关。单独的乳酸血症对细胞在缺糖状态下的存活没有影响；酸中毒单独可以延长细胞的存活时间，但不如乳酸酸中毒有效。因此，癌细胞抵抗葡萄糖剥夺诱导的细胞死亡的能力至少部分是由乳酸酸中毒引起的，我们可以预见，破坏乳酸酸中毒可能会恢复癌细胞对葡萄糖剥夺的敏感性。版权所有(C)2012年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Solid tumours are dependent on glucose, but are generally glucose-deprived due to poor vascularization. Nevertheless, cancer cells can generally survive glucose deprivation better than their normal counterparts. Thus, to render cancer cells sensitive to glucose depletion may potentially provide an effective strategy for cancer intervention. We propose that lactic acidosis, a tumour microenvironment factor, may allow cancer cells to develop resistance to glucose deprivation-induced death, and that disruption of lactic acidosis may resume cancer cells' sensitivity to glucose depletion. Lactic acidosis, lactosis, or acidosis was generated by adding pure lactic acid, sodium lactate, or HCl to the culture medium. Cell death, cell cycle, autophagy, apoptosis, and gene expression profiling of the surviving cancer cells under glucose deprivation with lactic acidosis were determined. Under glucose deprivation without lactic acidosis, 90% of 4T1 cancer cells died within a single day; in a sharp contrast, under lactic acidosis, 90% of 4T1 cells died in a period of 10 days, with viable cells identified even 65 days after glucose was depleted. Upon glucose restoration, surviving cells resumed proliferation. Lactic acidosis also significantly extended survival of other cancer cells under glucose deprivation. G1/G0 arrest, autophagy induction, and apoptosis inhibition were tightly associated with lactic acidosis-mediated resistance to glucose deprivation. Lactosis alone had no effect on cell survival under glucose deprivation; acidosis alone can prolong cell survival time but is not as potent as lactic acidosis. Thus, the ability of cancer cells to resist glucose deprivation-induced cell death is conferred, at least in part, by lactic acidosis, and we envision that disrupting the lactic acidosis may resume the sensitivity of cancer cells to glucose deprivation. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.