Metabolic adaptation to hypoxia: do worms and cancer cells share common metabolic responses to hypoxic stress?
Metabolic adaptation to hypoxia: do worms and cancer cells share common metabolic responses to hypoxic stress?
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DOI：
10.1038/s41418-021-00741-y
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发表时间：
2021-04
影响因子：
12.4
通讯作者：
Heimbucher T
中科院分区：
文献类型：
--
作者：
Baumeister R;Murphy CT;Heimbucher T
后生动物物种的生存依赖于氧气供需的复杂平衡。在人类中，这种平衡在与年龄有关的疾病（包括心血管系统疾病和癌症）中被扰乱。快速生长的癌细胞在缺乏功能性血管系统的情况下变得缺氧。由此产生的氧气和营养压力导致基本代谢途径的重新布线，以确保缺氧肿瘤区域中的细胞存活，这些区域通常包含最恶性的肿瘤细胞。因此，破译保持低氧细胞存活的代谢机制对于改善癌症治疗至关重要。在最近的一项研究中，线虫C.秀丽隐杆线虫已被用作通过代谢变化分析低氧适应的模型[1]。C.秀丽线虫是一种合适的模式生物，以剖析赋予低氧适应的机制。作为一种土壤生活线虫，它可以在低氧环境中生存，甚至在缺氧条件下，进入假死状态[2]。假死是一种可逆的低代谢状态，是研究缺氧生物体代谢变化的理想方法。在线虫的研究中，C2 H2锌指（ZF）转录因子PQM-1被鉴定为脂质和碳水化合物代谢以及线虫缺氧存活的调节剂[1]。PQM-1活性的丧失延长了缺氧蠕虫的存活时间，这与代谢变化有关。缺氧pqm-1功能丧失突变体显示脂肪水平降低和糖原量增加，表明PQM-1活性可能正常促进脂质积累，然而，在缺氧中抑制糖原水平（图1）。因此，PQM-1活性的下调或丧失似乎调节了从脂肪到糖原的代谢转换，这与低氧应激中蠕虫的存活率提高有关。以往的研究结果表明，C。elegans存储
The survival of metazoan species is dependent on an intricate balance of oxygen supply and demand. In humans this balance is disturbed during age-related diseases including disorders of the cardiovascular system and cancer. Rapidly growing cancer cells become hypoxic in the absence of a functional vascular system. The resulting oxygen and nutrient stress causes rewiring of essential metabolic pathways to ensure survival of cells in hypoxic tumor areas, which often contain the most malignant tumor cells. Thus, deciphering metabolic mechanisms keeping hypoxic cells alive is critical for improving cancer therapies. In a recent study, the nematode C. elegans has been utilized as a model to analyze hypoxic adaptation through changes in metabolism [1]. C. elegans is a suitable model organism to dissect mechanisms conferring hypoxic adaptation. As a soil-living nematode, it can survive in low oxygen environments, even in anoxic conditions, by entering suspended animation [2]. Suspended animation is a reversible, hypometabolic state, ideal to investigate metabolic changes of a hypoxic organism.In the recent C. elegans study, the C2H2 zinc-finger (ZF) transcription factor PQM-1 was identified as a regulator of lipid and carbohydrate metabolism and nematodes’ hypoxic survival [1]. Loss of PQM-1 activity extended survival of hypoxic worms, which correlated with metabolic changes. Hypoxic pqm-1 loss-of-function mutants displayed decreased fat levels and increased amount of glycogen, indicating that PQM-1 activity likely normally promotes lipid accumulation, however, represses glycogen levels in hypoxia (Fig. 1). Thus, downregulation or loss of PQM-1 activity appears to regulate a metabolic switch from fat to glycogen, which is associated with an improved survival of worms in hypoxic stress. Previous findings demonstrate that the ability of C. elegans to store
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