近日,，來自美國弗雷德里克國家癌癥研究所的研究人員James M. Phang等人發(fā)現(xiàn),，致癌轉(zhuǎn)錄因子c-MYC能夠改變脯氨酸及谷氨酰胺之間的代謝過程，促進c-MYC所調(diào)節(jié)的細胞增生及代謝反應(yīng),。相關(guān)研究成果于5月21日發(fā)表在美國《國家科學院院刊》（PNAS）上。
研究發(fā)現(xiàn)，除了糖酵解以外,，致癌轉(zhuǎn)錄因子c-MYC也能刺激谷氨酰胺的代謝。通過上調(diào)谷氨酰胺酶(GLS),，促進能量生成,，結(jié)果促進了癌細胞的增生。
眾所周知,，谷氨酰胺能夠通過GLS轉(zhuǎn)化為谷氨酸,，進入三羧酸循環(huán)后成為一種重要的能量來源。但是,，很少有人知道,，谷氨酸酯能夠通過5-羧酸Δ1-吡咯啉(P5C)轉(zhuǎn)化為脯氨酸。這項研究發(fā)現(xiàn)，一些由MYC誘導(dǎo)的細胞內(nèi)作用正是因為MYC調(diào)節(jié)了脯氨酸的代謝所致,。
脯氨酸氧化酶,，通常也被稱為脯氨酸脫氫酶(POX/PRODH)，是脯氨酸分解代謝途經(jīng)里的第一種酶,，同時也是一種線粒體的腫瘤抑制因子,，能夠抑制細胞增生，并誘導(dǎo)細胞凋亡,。
MiR-23b*和miR-23b加工來源于相同的轉(zhuǎn)錄產(chǎn)物,，miR-23b能夠抑制GLS的翻譯。研究發(fā)現(xiàn),，在人腎腫瘤里,，MiR-23b*介導(dǎo)了POX/PRODH的下調(diào)。
利用MYC誘導(dǎo)的人Burkitt淋巴瘤模型P493及PC3人前列腺癌細胞,，研究人員發(fā)現(xiàn),，MYC主要通過上調(diào)miR-23b*，抑制了POX/PRODH的表達,。敲除POX/PRODH以后,，缺乏MYC所引起的生長抑制作用能夠被部分逆轉(zhuǎn)。這表明,，對由MYC介導(dǎo)的細胞內(nèi)作用,，抑制POX/PRODH具有重要意義。
有趣的是,，MYC不僅抑制了POX/PRODH,，也顯著的增加了由谷氨酰胺合成脯氨酸的酶，包括P5C合酶及P5C還原酶1,。
利用13C,15N-谷氨酰胺作為一個示蹤物,，研究人員確定了MYC誘導(dǎo)的脯氨酸的合成是來源于谷氨酰胺。James M. Phang表示,，這種被MYC賦予的谷氨酰胺與脯氨酸之間的代謝關(guān)系,，突出強調(diào)了腫瘤代謝的復(fù)雜性。
因此,，為了深層次的理解腫瘤代謝機制,，進一步研究谷氨酰胺與脯氨酸之間的代謝聯(lián)系還十分必要。并且,，這對發(fā)展新的腫瘤治療策略也是大有裨益的,。（生物谷Deepblue編譯）
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.
