PNAS：发现新的肿瘤代谢机制

近日，来自美国弗雷德里克国家癌症研究所的研究人员James M. Phang等人发现，致癌转录因子c-MYC能够改变脯氨酸及谷氨酰胺之间的代谢过程，促进c-MYC所调节的细胞增生及代谢反应。相关研究成果于5月21日发表在美国《国家科学院院刊》（PNAS）上。

研究发现，除了糖酵解以外，致癌转录因子c-MYC也能刺激谷氨酰胺的代谢。通过上调谷氨酰胺酶(GLS)，促进能量生成，结果促进了癌细胞的增生。

众所周知，谷氨酰胺能够通过GLS转化为谷氨酸，进入三羧酸循环后成为一种重要的能量来源。但是，很少有人知道，谷氨酸酯能够通过5-羧酸Δ^1-吡咯啉(P5C)转化为脯氨酸。这项研究发现，一些由MYC诱导的细胞内作用正是因为MYC调节了脯氨酸的代谢所致。

脯氨酸氧化酶，通常也被称为脯氨酸脱氢酶(POX/PRODH)，是脯氨酸分解代谢途经里的第一种酶，同时也是一种线粒体的肿瘤抑制因子，能够抑制细胞增生，并诱导细胞凋亡。

MiR-23b*和miR-23b加工来源于相同的转录产物，miR-23b能够抑制GLS的翻译。研究发现，在人肾肿瘤里，MiR-23b*介导了POX/PRODH的下调。

利用MYC诱导的人Burkitt淋巴瘤模型P493及PC3人前列腺癌细胞，研究人员发现，MYC主要通过上调miR-23b*，抑制了POX/PRODH的表达。敲除POX/PRODH以后，缺乏MYC所引起的生长抑制作用能够被部分逆转。这表明，对由MYC介导的细胞内作用，抑制POX/PRODH具有重要意义。

有趣的是，MYC不仅抑制了POX/PRODH，也显著的增加了由谷氨酰胺合成脯氨酸的酶，包括P5C合酶及P5C还原酶1。

利用¹³C,¹⁵N-谷氨酰胺作为一个示踪物，研究人员确定了MYC诱导的脯氨酸的合成是来源于谷氨酰胺。James M. Phang表示，这种被MYC赋予的谷氨酰胺与脯氨酸之间的代谢关系，突出强调了肿瘤代谢的复杂性。

因此，为了深层次的理解肿瘤代谢机制，进一步研究谷氨酰胺与脯氨酸之间的代谢联系还十分必要。并且，这对发展新的肿瘤治疗策略也是大有裨益的。（生物谷Deepblue编译）

doi: 10.1073/pnas.1203244109
PMC:
PMID:

Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC

Wei Liu, Anne Leb, Chad Hancock, Andrew N. Lane, Chi V. Dang, Teresa W.-M. Fan, and James M. Phang.

In addition to glycolysis, the oncogenic transcription factor c-MYC (MYC) stimulates glutamine catabolism to fuel growth and proliferation of cancer cells through up-regulating glutaminase (GLS).Glutamine is converted to glutamate by GLS, entering the tricarboxylic acid cycle as an important energy source. Less well-recognized, glutamate can also be converted to proline through Δ1-pyrroline-5-carboxylate (P5C) and vice versa. This study suggests that some MYC-induced cellular effects are due to MYC regulation of proline metabolism.Proline oxidase, also known as proline dehydrogenase (POX/PRODH), the first enzyme in proline catabolism, is a mitochondrial tumor suppressor that inhibits proliferation and induces apoptosis. MiR-23b* mediates POX/PRODH down-regulation in human kidney tumors. MiR-23b* is processed from the same transcript as miR-23b; the latter inhibits the translation of GLS.Using MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells, we showed that MYC suppressed POX/PRODH expression primarily through up-regulating miR-23b*. The growth inhibition in the absence of MYC was partially reversed by POX/PRODH knockdown, indicating the importance of suppression of POX/PRODH in MYC-mediated cellular effects.Interestingly, MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. MYC-induced proline biosynthesis from glutamine was directly confirmed using 13C,15N-glutamine as a tracer. The metabolic link between glutamine and proline afforded by MYC emphasizes the complexity of tumor metabolism.Further studies of the relationship between glutamine and proline metabolism should provide a deeper understanding of tumor metabolism while enabling the development of novel therapeutic strategies.