Proline oxidase promotes tumor cell survival in hypoxic tumor microenvironments.
Proline oxidase promotes tumor cell survival in hypoxic tumor microenvironments.
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DOI：
10.1158/0008-5472.can-12-0080
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发表时间：
2012-07-15
期刊：
影响因子：
11.2
通讯作者：
Phang JM
中科院分区：
文献类型：
--
作者：
Liu W;Glunde K;Bhujwalla ZM;Raman V;Sharma A;Phang JM
脯氨酸是一种容易释放的应激底物，其可以被脯氨酸氧化酶（POX）代谢以在营养应激期间产生活性氧类以诱导细胞凋亡或自噬或ATP。然而，尚未探讨脯氨酸代谢对缺氧微环境中肿瘤发生的贡献。在这项研究中，我们研究了不同功能的POX缺氧和葡萄糖耗竭。我们发现，缺氧诱导POX表达的癌细胞在体外和POX上调共定位与缺氧组织在体内。此外，低氧和低糖的组合显示出对POX表达的累加效应。与低糖条件相似，缺氧诱导的POX依赖于AMP激活的蛋白激酶（AMPK）的激活，而不依赖于HIF-1α和HIF-2α。在低葡萄糖和组合的低葡萄糖和缺氧条件下，脯氨酸分解代谢的POX优先用于ATP的生产，而在缺氧下，POX介导的自噬信号的生存产生ROS。尽管缺氧和葡萄糖剥夺的具体机制不同，但POX始终有助于肿瘤细胞在这些条件下的存活。总之，我们的研究结果为存在于敌对微环境中的肿瘤细胞的代谢重编程提供了新的见解，并表明脯氨酸代谢是癌症治疗的潜在靶点。
Proline is a readily released stress substrate that can be metabolized by proline oxidase (POX) to generate either reactive oxygen species to induce apoptosis or autophagy or ATP during times of nutrient stress. However, the contribution of proline metabolism to tumorigenesis in hypoxic microenvironments has not been explored. In this study, we investigated the different functions of POX under hypoxia and glucose depletion. We found that hypoxia induced POX expression in cancer cells in vitro and that POX upregulation co-localized with hypoxic tissues in vivo. In addition, the combination of hypoxia and low-glucose showed additive effects on POX expression. Similar to conditions of low glucose, hypoxia-mediated POX induction was dependent on AMP-activated protein kinase (AMPK) activation, but was independent of HIF-1α and HIF-2α. Under low-glucose and combined low-glucose and hypoxic conditions, proline catabolized by POX was used preferentially for ATP production, whereas under hypoxia, POX mediated autophagic signaling for survival by generating ROS. Although the specific mechanism was different for hypoxia and glucose deprivation, POX consistently contributed to tumor cell survival under these conditions. Together, our findings offer new insights into the metabolic reprogramming of tumor cells present within a hostile microenvironment and suggest that proline metabolism is a potential target for cancer therapeutics.