Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; Division of Cardiovascular Medicine, Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Departments of Medicine and Pharmacology, University of California, San Diego, 9500 Gilman Avenue, La Jolla, CA 92093, USA.
Cell Rep. 2019 Feb 12;26(7):1691-1700.e5. doi: 10.1016/j.celrep.2019.01.059.
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 G and SGM 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 SGM 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 GM 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.
细胞周期调控和细胞代谢的改变与癌症转化有关，细胞周期中活跃的酶可能代表癌细胞的弱点。在这里，我们通过细胞分选与基于质谱的同位素示踪相结合，绘制了 G 和 SGM 期的代谢事件图谱，揭示了数百种与细胞周期相关的代谢物。特别是，在 SGM 期，转化细胞而非正常细胞中精氨酸摄取和鸟氨酸合成是活跃的，线粒体精氨酸酶 2 (ARG2) 酶是一种潜在的机制。虽然癌细胞专门使用 ARG2，但正常上皮细胞通过鸟氨酸转氨酶 (OAT) 合成鸟氨酸。ARG2 的敲低显著降低了癌细胞的生长并导致 GM 期停滞，而不会通过 OAT 诱导代偿。在人类肿瘤中，ARG2 在特定肿瘤类型中高度表达，包括基底样乳腺癌。这项研究揭示了代谢和细胞周期之间的相互作用，并将 ARG2 鉴定为潜在的代谢靶点。
