Phang James M, Liu Wei, Hancock Chad N, Fischer Joseph W
Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
Curr Opin Clin Nutr Metab Care. 2015 Jan;18(1):71-7. doi: 10.1097/MCO.0000000000000121.
Proline metabolism impacts a number of regulatory targets in both animals and plants and is especially important in cancer. Glutamine, a related amino acid, is considered second in importance only to glucose as a substrate for tumors. But proline and glutamine are interconvertible and linked in their metabolism. In animals, proline and glutamine have specific regulatory functions and their respective physiologic sources. A comparison of the metabolism of proline and glutamine would help us understand the importance of these two nonessential amino acids in cancer metabolism.
The regulatory functions of proline metabolism proposed 3 decades ago have found relevance in many areas. For cancer, these functions play a role in apoptosis, autophagy and in response to nutrient and oxygen deprivation. Importantly, proline-derived reactive oxygen species served as a driving signal for reprogramming. This model has been applied by others to metabolic regulation for the insulin-prosurvival axis, induction of adipose triglyceride lipase for lipid metabolism and regulation of embryonic stem cell development. Of special interest, modulatory proteins such as parkinson protein 7 and oral cancer overexpressed 1 interact with pyrroline-5-carboxylate reductase, a critical component of the proline regulatory axis. Although the interconvertibility of proline and glutamine has been long established, recent findings showed that the proto-oncogene, cellular myelocytomatosis oncogene, upregulates glutamine utilization (glutaminase) and routes glutamate to proline biosynthesis (pyrroline-5-carboxylate synthase, pyrroline-5-carboxylate reductases). Additionally, collagen, which contains large amounts of proline, may be metabolized to serve as a reservoir for proline. This metabolic relationship as well as the new regulatory targets of proline metabolism invites an elucidation of the differential effects of these nonessential amino acids and their production, storage and mobilization.
Mechanisms by which the proline regulatory axis modulates the cancer phenotype are being revealed. Proline can be synthesized from glutamine as well as derived from collagen degradation. The metabolism of proline serves as a source of energy during stress, provides signaling reactive oxygen species for epigenetic reprogramming and regulates redox homeostasis.
脯氨酸代谢影响动物和植物中的许多调控靶点，在癌症中尤为重要。谷氨酰胺是一种相关氨基酸，被认为是仅次于葡萄糖的肿瘤重要底物。但脯氨酸和谷氨酰胺在代谢中是可相互转化且相互关联的。在动物中，脯氨酸和谷氨酰胺具有特定的调节功能及其各自的生理来源。比较脯氨酸和谷氨酰胺的代谢有助于我们理解这两种非必需氨基酸在癌症代谢中的重要性。
30年前提出的脯氨酸代谢调节功能在许多领域都具有相关性。对于癌症而言，这些功能在细胞凋亡、自噬以及对营养和氧剥夺的反应中发挥作用。重要的是，脯氨酸衍生的活性氧作为重编程的驱动信号。该模型已被其他人应用于胰岛素促存活轴的代谢调节、脂质代谢中脂肪甘油三酯脂肪酶的诱导以及胚胎干细胞发育的调节。特别值得关注的是，诸如帕金森蛋白7和口腔癌过表达蛋白1等调节蛋白与脯氨酸调节轴的关键成分吡咯啉-5-羧酸还原酶相互作用。尽管脯氨酸和谷氨酰胺的相互转化早已确立，但最近的研究结果表明，原癌基因、细胞髓细胞瘤癌基因会上调谷氨酰胺利用（谷氨酰胺酶）并将谷氨酸导向脯氨酸生物合成途径（吡咯啉-5-羧酸合酶、吡咯啉-5-羧酸还原酶）。此外，含有大量脯氨酸的胶原蛋白可能被代谢以作为脯氨酸的储存库。这种代谢关系以及脯氨酸代谢的新调控靶点促使人们阐明这些非必需氨基酸的差异效应及其产生、储存和动员。
脯氨酸调节轴调节癌症表型的机制正在被揭示。脯氨酸可由谷氨酰胺合成，也可来源于胶原蛋白降解。脯氨酸代谢在应激期间作为能量来源，为表观遗传重编程提供信号活性氧，并调节氧化还原稳态。
