Proline oxidase functions as a mitochondrial tumor suppressor in human cancers.
Proline oxidase functions as a mitochondrial tumor suppressor in human cancers.
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DOI：
10.1158/0008-5472.can-09-1223
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发表时间：
2009-08-15
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 Y;Borchert GL;Donald SP;Diwan BA;Anver M;Phang JM
肿瘤代谢和生物能量学已成为癌症研究的重要课题，并且是抗癌治疗的有前景的靶点。尽管葡萄糖是主要的能量来源，但脯氨酸作为一种替代底物也很重要，尤其是在营养应激期间。脯氨酸氧化酶（POX）催化脯氨酸分解代谢的第一步，由p53诱导，能够调节细胞存活以及介导程序性细胞死亡。在小鼠异种移植肿瘤模型中，我们发现POX通过导致G2细胞周期阻滞极大地减少了肿瘤的形成。此外，免疫组织化学染色显示肿瘤组织中POX表达降低。重要的是，由于α - 酮戊二酸产量增加（α - 酮戊二酸是脯氨酰羟化和HIF - 1α降解的关键底物），HIF - 1α信号传导随着POX表达而受损。结合先前的体外研究结果以及已报道的临床遗传关联，这些新发现使我们提出POX是一种线粒体肿瘤抑制因子以及癌症治疗的潜在靶点。
Tumor metabolism and bioenergetics have become important topics for cancer research and are promising targets for anticancer therapy. Although glucose serves as the main source of energy, proline, an alternative substrate, is important, especially during nutrient stress. Proline oxidase (POX), catalyzing the first step in proline catabolism, is induced by p53 and can regulate cell survival as well as mediate programmed cell death. In a mouse xenograft tumor model, we found that POX greatly reduced tumor formation by causing G2 cell cycle arrest. Furthermore, immunohistochemical staining showed decreased POX expression in tumor tissues. Importantly, HIF-1α signaling was impaired with POX expression due to the increased production of α-ketoglutarate, a critical substrate for prolyl hydroxylation and degradation of HIF-1α. Combined with previous in vitro findings and reported clinical genetic associations, these new findings lead us to propose POX as a mitochondrial tumor suppressor and a potential target for cancer therapy.