Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides.
Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides.
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脯氨酸生物合成增强了肿瘤细胞的生长和有氧糖酵解：吡啶核苷酸的参与。
DOI：
10.1038/srep17206
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发表时间：
2015-11-24
影响因子：
4.6
通讯作者：
Phang JM
中科院分区：
文献类型：
--
作者：
Liu W;Hancock CN;Fischer JW;Harman M;Phang JM
非必需氨基酸脯氨酸的代谢有助于肿瘤代谢重编程。以前我们发现MYC增加了谷氨酰胺的脯氨酸生物合成（PB）。我们发现MYC在蛋白和mRNA水平上增加了PB中酶的表达。阻断PB可降低肿瘤细胞生长和能量产生。添加Δ1-pyrroline-5-carboxylate （P5C）或脯氨酸可逆转P5C合酶敲低的作用，但不能逆转P5C还原酶敲低的作用。重要的是，脯氨酸的逆转作用被伴随的脯氨酸脱氢酶/氧化酶（PRODH/POX）敲低阻断。这些发现表明，PB对肿瘤生长的重要调节作用来自脯氨酸和P5C之间的代谢循环，而不是产物脯氨酸或中间产物P5C。通过将脯氨酸循环连接到糖酵解和戊糖磷酸途径的氧化臂，我们进一步证明了PB在维持吡啶核苷酸水平方面的关键作用。这些发现确立了PB在肿瘤发生中的新功能，将葡萄糖、谷氨酰胺和吡啶核苷酸的重编程联系起来，并可能为抗肿瘤治疗提供新的靶点。
The metabolism of the nonessential amino acid proline contributes to tumor metabolic reprogramming. Previously we showed that MYC increases proline biosynthesis (PB) from glutamine. Here we show MYC increases the expression of the enzymes in PB at both protein and mRNA levels. Blockade of PB decreases tumor cell growth and energy production. Addition of Δ1-pyrroline-5-carboxylate (P5C) or proline reverses the effects of P5C synthase knockdown but not P5C reductases knockdown. Importantly, the reversal effect of proline was blocked by concomitant proline dehydrogenase/oxidase (PRODH/POX) knockdown. These findings suggest that the important regulatory contribution of PB to tumor growth derives from metabolic cycling between proline and P5C rather than product proline or intermediate P5C. We further document the critical role of PB in maintaining pyridine nucleotide levels by connecting the proline cycle to glycolysis and to the oxidative arm of the pentose phosphate pathway. These findings establish a novel function of PB in tumorigenesis, linking the reprogramming of glucose, glutamine and pyridine nucleotides, and may provide a novel target for antitumor therapy.