釜底抽“氨”可抑制乳腺癌生长

　　营养素消耗增加可以提供碳、氮、氧、硫，以适应快速繁殖细胞（例如癌细胞）大量的生物能、生物合成、促生存需求。随后，此类快速繁殖的细胞产生大量代谢废物，通过排泄系统清除。然而，在肿瘤微环境中，代谢废物（例如乳酸、氨）不断蓄积。氨，又称阿摩尼亚，是普遍存在于细胞代谢过程的副产物，但是氨产生的生物学影响尚不明确，尤其对于癌症。

　　2017年10月12日，美国科学促进会《科学》在线发表哈佛医学院、麻省理工学院与哈佛大学布罗德研究所的研究报告，发现氨不仅是一种有毒废物，而且循环于氨基酸代谢核心，以最大程度地利用氮。

　　癌细胞主要通过谷氨酸脱氢酶促进还原性氨基化反应吸收氨，继发反应使其他氨基酸（例如脯氨酸和天冬氨酸）直接从中获得氮。

　　该研究发现，氨代谢循环可以加速乳腺癌生长。在小鼠中，氨蓄积于肿瘤微环境，通过谷氨酸脱氢酶活性直接被用于产生氨基酸。

　　因此，氨不仅是被分泌的废物，而且可以为肿瘤生长提供最重要的氮源。如果阻断乳腺癌微环境氨代谢循环，例如靶向抑制乳腺癌的谷氨酸脱氢酶，就有可能釜底抽“氨”，抑制乳腺癌生长。该研究结果为乳腺癌的营养代谢预防和营养代谢靶向治疗奠定了重要基础。

Science. 2017 Oct 12. [Epub ahead of print]

Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass.

Jessica B. Spinelli, Haejin Yoon, Alison E. Ringel, Sarah Jeanfavre, Clary B. Clish, Marcia C. Haigis.

Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Ammonia is a ubiquitous by-product of cellular metabolism, however the biological consequences of ammonia production are not fully understood, especially in cancer. We find that ammonia is not merely a toxic waste product, but is recycled into central amino acid metabolism to maximize nitrogen utilization. Cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH), and secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment, and was used directly to generate amino acids through GDH activity. These data show that ammonia not only is a secreted waste product, but a fundamental nitrogen source that can support tumor biomass.

DOI: 10.1126/science.aam9305