Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs.
Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs.
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DOI：
10.1158/0008-5472.can-11-2076
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发表时间：
2012-01-15
期刊：
影响因子：
11.2
通讯作者：
Chi JT
中科院分区：
文献类型：
--
作者：
Tang X;Lucas JE;Chen JL;LaMonte G;Wu J;Wang MC;Koumenis C;Chi JT
在实体瘤微环境中，乳酸酸中毒和缺氧各自对癌症病理生理学具有强大的影响。然而，这些过程对彼此的影响是未知的。在这里，我们报告说，一个显着的一部分，在癌细胞引起的缺氧的转录反应被取消同时暴露于乳酸酸中毒。特别是，乳酸酸中毒破坏了通常在缺氧条件下发生的HIF-1α蛋白的稳定性。与此相反，乳酸酸中毒强烈协同缺氧激活未折叠蛋白反应（UPR）和炎症反应，表现出很强的相似性ATF 4驱动的氨基酸剥夺反应（AAR）。在某些乳腺肿瘤和乳腺肿瘤细胞检查，基因表达和阵列CGH数据的综合分析显示，DNA拷贝数的改变在ATF 4基因座，一个重要的激活剂的UPR/AAR途径。在这种情况下，不同的ATF 4水平影响暴露于缺氧和乳酸酸中毒后细胞的存活。我们的研究结果表明，在实体瘤中存在的乳酸酸中毒的条件抑制典型的缺氧反应，激活UPR和炎症反应。此外，他们认为ATF 4状态可能是癌细胞适应肿瘤微环境中氧气和酸度波动能力的关键决定因素，可能将短期转录反应与癌细胞中拷贝数改变的长期选择联系起来。
Within solid tumor microenvironments, lactic acidosis and hypoxia each have powerful effects on cancer pathophysiology. However, the influence that these processes exert on each other is unknown. Here we report that a significant portion of the transcriptional response to hypoxia elicited in cancer cells is abolished by simultaneous exposure to lactic acidosis. In particular, lactic acidosis abolished stabilization of HIF-1α protein which occurs normally under hypoxic conditions. In contrast, lactic acidosis strongly synergized with hypoxia to activate the unfolded protein response (UPR) and an inflammatory response, displaying a strong similarity to ATF4-driven amino acid deprivation responses (AAR). In certain breast tumors and breast tumor cells examined, an integrative analysis of gene expression and array CGH data revealed DNA copy number alterations at the ATF4 locus, an important activator of the UPR/AAR pathway. In this setting, varying ATF4 levels influenced the survival of cells after exposure to hypoxia and lactic acidosis. Our findings reveal that the condition of lactic acidosis present in solid tumors inhibits canonical hypoxia responses and activates UPR and inflammation responses. Further, they suggest that ATF4 status may be a critical determinant of the ability of cancer cells to adapt to oxygen and acidity fluctuations in the tumor microenvironment, perhaps linking short-term transcriptional responses to long-term selection for copy number alterations in cancer cells.