Proline dehydrogenase (oxidase), a mitochondrial tumor suppressor, and autophagy under the hypoxia microenvironment
Proline dehydrogenase (oxidase), a mitochondrial tumor suppressor, and autophagy under the hypoxia microenvironment
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DOI：
10.4161/auto.21152
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发表时间：
2012-09-01
期刊：
影响因子：
13.3
通讯作者：
Phang, James M.
中科院分区：
文献类型：
--
作者：
Liu, Wei;Phang, James M.
脯氨酸脱氢酶（氧化酶，PRODH/POX）是脯氨酸催化途径中的第一个酶，已被鉴定为线粒体代谢肿瘤抑制因子，其在多种人类肿瘤中下调。然而，我们最近的研究结果表明，PRODH/POX是上调缺氧在体外和体内。低葡萄糖和缺氧的组合对PRODH/POX表达产生累加效应。缺氧和葡萄糖消耗都通过AMP激活的蛋白激酶（AMPK）激活来增强PRODH/POX表达以促进肿瘤细胞存活。然而，PRODH/POX促生存功能的机制在缺氧和低糖条件下是不同的。在缺氧或不缺氧的情况下，葡萄糖消耗提高了PRODH/POX和脯氨酸的利用率，以供应细胞能量需求的ATP。有趣的是，在缺氧条件下，PRODH/POX通过产生活性氧（ROS）诱导保护性自噬。AMPK是应激触发的自噬的主要启动子。因此，PRODH/POX作为AMPK的下游效应物在缺氧条件下激活自噬。这种调节被证实是独立的雷帕霉素（MTOR）途径，一个主要的下游目标AMPK信号转导的机制的目标。
Proline dehydrogenase (oxidase, PRODH/POX), the first enzyme in the pathway of proline catabolism, has been identified as a mitochondrial, metabolic tumor suppressor, which is downregulated in a variety of human tumors. However, our recent findings show that PRODH/POX is upregulated by hypoxia in vitro and in vivo. The combination of low glucose and hypoxia produces additive effects on PRODH/POX expression. Both hypoxia and glucose depletion enhance PRODH/POX expression through AMP-activated protein kinase (AMPK) activation to promote tumor cell survival. Nevertheless, the mechanisms underlying PRODH/POX prosurvival functions are different for hypoxia and low-glucose conditions. Glucose depletion with or without hypoxia elevates PRODH/POX and proline utilization to supply ATP for cellular energy needs. Interestingly, under hypoxia PRODH/POX induces protective autophagy by generating reactive oxygen species (ROS). AMPK is the main initiator of stress-triggered autophagy. Thus, PRODH/POX acts as a downstream effector of AMPK in the activation of autophagy under hypoxia. This regulation was confirmed to be independent of the mechanistic target of rapamycin (MTOR) pathway, a major downstream target of AMPK signaling.