Nutritional Stress and Arginine Auxotrophy Confer High Sensitivity to Chloroquine Toxicity in Mesothelioma Cells
Nutritional Stress and Arginine Auxotrophy Confer High Sensitivity to Chloroquine Toxicity in Mesothelioma Cells
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DOI：
10.1165/rcmb.2011-0195oc
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发表时间：
2012-04-01
影响因子：
6.4
通讯作者：
Palumbo, Camilla
中科院分区：
文献类型：
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作者：
Battisti, Sonia;Valente, Davide;Palumbo, Camilla
细胞对自噬抑制剂（如氯喹（CQ））的敏感性与参与自噬控制和执行的分子的表达/活性之间的相关性已得到充分证实。然而，具有可比自噬潜力的肿瘤细胞可能会显示不同程度的自噬成瘾，这是由于分子决定簇的差异表达，这仍然很少被定义。在这项研究中，我们研究了CQ对恶性间皮瘤细胞系的生长，死亡和自噬活性的影响，这些细胞系在标准与营养应激条件下培养，部分模拟肿瘤微环境中发现的那些。我们报告说，在每个细胞系中，CQ的毒性作用被营养应激放大，并被自噬抑制抑制。尽管如此，细胞系显示出不同水平的敏感性CQ毒性，这并不与它们的相对程度的组成性和营养应激诱导的自噬，也与药物诱导的自噬抑制的相对幅度。因此，我们测试了细胞系对CQ的敏感性与其对细胞内成分通过自噬再循环的可变依赖性有关的假设。事实上，对CQ的毒性作用具有最高敏感性的细胞系是精氨酸营养缺陷型的，这是由于乙酰氨基琥珀酸合成酶（ASS）的表达缺陷。此外，ASS在这些细胞中的过表达降低了它们对CQ毒性的敏感性。基于这些结果，评估ASS在恶性间皮瘤组织中的表达可能有助于鉴别对该药物毒性作用敏感性增加的肿瘤亚组。
The correlation between cell sensitivity to autophagy inhibitors, such as chloroquine (CQ), and the expression/activity of molecules involved in the control and execution of autophagy is well documented. However, tumor cells with comparable autophagic potentials may display variable degrees of autophagy addiction, due to the differential expression of molecular determinants, which are still scarcely defined. In this study, we investigated the effects of CQ on growth, death, and autophagic activity of malignant mesothelioma cell lines cultured in standard versus nutritional stress conditions partially mimicking those found in the tumor microenvironment. We report that, in each cell line, the toxic effects of CQ were amplified by nutritional stress and paralleled by autophagy inhibition. Still, the cell lines displayed different levels of sensitivity to CQ toxicity, which did not correlate with their relative degrees of constitutive and nutritional stress-induced autophagy, nor with the relative magnitude of the autophagy inhibition induced by the drug. Thus, we tested the hypothesis that the cell lines' sensitivity to CQ was related to their variable dependence on recycling of intracellular constituents by autophagy. In fact, the cell line with the highest sensitivity to the toxic effects of CQ was auxotrophic for arginine, due to the deficient expression of the enzyme argininosuccinate synthetase (ASS). Furthermore, overexpression of ASS in these cells reduced their sensitivity to CQ toxicity. Based on these results, the assessment of ASS expression in malignant mesothelioma tissues may allow the identification of subgroups of tumors with an increased sensitivity to the toxic effects of this drug.