瑞典美国发现三阴性乳腺癌新靶点
癌细胞的有丝分裂循环过程又称细胞周期，可划分为静止期（G0）、DNA合成前期（G1）、DNA合成期（S）、DNA合成后期（G2）、分裂期（M）。细胞周期调节以及代谢的改变可以引起癌细胞转化，而活跃于细胞周期特定阶段的代谢酶，可能成为癌细胞的靶点。
2019年2月12日，美国《细胞》旗下《细胞报告》在线发表瑞典卡罗林斯卡医学院、卡罗林斯卡大学医院、美国圣地亚哥加利福尼亚大学的研究报告。
该研究通过细胞分离归类和代谢物质谱同位素示踪，分析了G1期与SG2M期的代谢事件分布情况，发现了数百种与细胞周期相关的代谢物。尤其，精氨酸的摄取和鸟氨酸的合成，活跃于癌细胞而非正常细胞的SG2M期，其潜在机制为线粒体精氨酸酶2（ARG2）。癌细胞仅仅通过ARG2合成鸟氨酸，而正常上皮细胞可以通过鸟氨酸转氨酶（OAT）合成鸟氨酸。抑制ARG2编码基因的表达水平，可以显著减少癌细胞生长，并停滞于G2M期，而无法通过OAT进行代偿。
此外，为了评定ARG2对于人类癌症的影响，该研究分析了超过2000例人类乳腺癌的ARG2表达水平，结果发现ARG2高表达于特定乳腺癌类型，例如雌激素受体阴性的基底样乳腺癌，并与患者不良生存结局密切相关，而雌激素受体阴性的基底样乳腺癌与三阴性乳腺癌高度交叉重叠。
因此，该研究结果表明，代谢与细胞周期之间存在相互影响，ARG2抑制剂有望成为三阴性乳腺癌的代谢靶向治疗方法，而不影响正常细胞的代谢和生长。
Cell Rep. 2019 Feb 12;26(7):1691-1700.e5.
Mapping Metabolic Events in the Cancer Cell Cycle Reveals Arginine Catabolism in the Committed SG2M Phase.
Irena Roci, Jeramie D. Watrous, Kim A. Lagerborg, Lorenzo Lafranchi, Arne Lindqvist, Mohit Jain, Roland Nilsson.
Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; University of California, San Diego, La Jolla, CA, USA.
HIGHLIGHTS
Cell sorting and metabolic tracing reveals cell-cycle-associated metabolites
Ornithine synthesis peaks during SG2M in transformed but not in normal cells
Cancer cells synthesize ornithine using ARG2 only, while normal cells use OAT
Knockdown of ARG2 suppresses cancer cell growth without compensation by OAT
Alterations in cell-cycle regulation and cellular metabolism are associated with cancer transformation, and enzymes active in the committed cell-cycle phase may represent vulnerabilities of cancer cells. Here, we map metabolic events in the G1 and SG2M phases by combining cell sorting with mass spectrometry-based isotope tracing, revealing hundreds of cell-cycle-associated metabolites. In particular, arginine uptake and ornithine synthesis are active during SG2M in transformed but not in normal cells, with the mitochondrial arginase 2 (ARG2) enzyme as a potential mechanism. While cancer cells exclusively use ARG2, normal epithelial cells synthesize ornithine via ornithine aminotransferase (OAT). Knockdown of ARG2 markedly reduces cancer cell growth and causes G2M arrest, while not inducing compensation via OAT. In human tumors, ARG2 is highly expressed in specific tumor types, including basal-like breast tumors. This study sheds light on the interplay between metabolism and cell cycle and identifies ARG2 as a potential metabolic target.
KEYWORDS: isotope tracing; mass spectrometry; cancer metabolism; ornithine; polyamines; arginase 2; ARG2; OAT; basal-like breast cancer
DOI: 10.1016/j.celrep.2019.01.059
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