The metabolism of proline, a stress substrate, modulates carcinogenic pathways
The metabolism of proline, a stress substrate, modulates carcinogenic pathways
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DOI：
10.1007/s00726-008-0063-4
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发表时间：
2008-11-01
期刊：
影响因子：
3.5
通讯作者：
Liu, Yongmin
中科院分区：
文献类型：
--
作者：
Phang, James M.;Donald, Steven P.;Liu, Yongmin
对肿瘤代谢的兴趣的复苏使得研究人员强调脯氨酸作为“应激底物”的代谢，并建议该途径作为潜在的抗肿瘤靶点。脯氨酸氧化酶，又名脯氨酸脱氢酶（POX/PRODH）催化脯氨酸降解的第一步，并使用脯氨酸产生用于存活的ATP或用于程序性细胞死亡的活性氧。POX/PRODH在基因毒性应激下由p53诱导，并通过线粒体和死亡受体途径启动细胞凋亡。此外，POX/PRODH由PPAR γ及其药理学配体噻唑烷二酮诱导。PPARgamma的抗肿瘤作用可能严重依赖于POX/PRODH。此外，它通过mTOR途径被营养应激上调以维持ATP水平。我们建议，脯氨酸是作为一个应力基板的降解胶原蛋白的微环境细胞外基质的基质金属蛋白酶。以类似于自噬的方式，这种来自细胞外基质中胶原蛋白的生物能量学的脯氨酸依赖性过程可以被称为“生态吞噬”。
The resurgence of interest in tumor metabolism has led investigators to emphasize the metabolism of proline as a "stress substrate" and to suggest this pathway as a potential anti-tumor target. Proline oxidase, a.k.a. proline dehydrogenase (POX/PRODH), catalyzes the first step in proline degradation and uses proline to generate ATP for survival or reactive oxygen species for programmed cell death. POX/PRODH is induced by p53 under genotoxic stress and initiates apoptosis by both mitochondrial and death receptor pathways. Furthermore, POX/PRODH is induced by PPAR gamma and its pharmacologic ligands, the thiazolidinediones. The anti-tumor effects of PPAR gamma may be critically dependent on POX/PRODH. In addition, it is upregulated by nutrient stress through the mTOR pathway to maintain ATP levels. We propose that proline is made available as a stress substrate by the degradation of collagen in the microenvironmental extracellular matrix by matrix metalloproteinases. In a manner analogous to autophagy, this proline-dependent process for bioenergetics from collagen in extracellular matrix can be designated "ecophagy".