Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Front Biosci (Landmark Ed). 2012 Jan 1;17(5):1835-45. doi: 10.2741/4022.
Proline plays a special role in cancer metabolism. Proline oxidase (POX), a.k.a. proline dehydrogenase (PRODH), is among a few genes induced rapidly and robustly by P53, the tumor suppressor. Ectopic expression of POX under control of tet-off promoter initiated mitochondrial apoptosis. The mechanism activated by POX is mediated by its production of ROS. In immunodeficient mice, POX overexpression markedly retarded growth of xenograft tumors. In human tumors of the digestive tract and kidney, POX was markedly decreased, suggesting that the suppressive effect of POX was downregulated. This was not due to POX gene mutations or hypermethylation. Instead, a microRNA, miR-23b*, expressed at high levels in tumors, was a potent inhibitor of POX expression. Furthermore, antagomirs of miR-23b* reversed the downregulated expression of POX and its tumor-suppressive effect, thereby providing a therapeutic strategy. POX not only responds to genotoxic stress, but also to inflammatory and metabolic stress. Depending on microenvironmental and temporal factors, POX can mediate oppositely-directed responses-programmed cell death, on the one hand, and survival, on the other.
脯氨酸在癌症代谢中起着特殊作用。脯氨酸氧化酶（POX），也称为脯氨酸脱氢酶（PRODH），是少数几种能被肿瘤抑制因子 P53 快速而强烈诱导的基因之一。在 tet-off 启动子的控制下，POX 的异位表达会引发线粒体凋亡。POX 激活的机制是通过其产生的 ROS 介导的。在免疫缺陷小鼠中，POX 的过表达显著延缓了异种移植肿瘤的生长。在消化道和肾脏的人类肿瘤中，POX 的表达明显降低，这表明 POX 的抑制作用被下调。这不是由于 POX 基因突变或高甲基化。相反，在肿瘤中高表达的 microRNA，miR-23b*，是 POX 表达的有效抑制剂。此外，miR-23b*的反义寡核苷酸逆转了下调的 POX 表达及其肿瘤抑制作用，从而提供了一种治疗策略。POX 不仅对遗传毒性应激有反应，而且对炎症和代谢应激也有反应。根据微环境和时间因素，POX 可以介导相反的反应——程序性细胞死亡，一方面，和存活，另一方面。
