Mapping Metabolic Events in the Cancer Cell Cycle Reveals Arginine Catabolism in the Committed SG2M Phase

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. [Display omitted] •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 Here, Roci et al. map metabolic events in the G1 and SG2M cell cycle phases, and show that arginase 2 (ARG2) is critical for cancer cell progression through SG2M. As proliferating cells are vulnerable during SG2M phase, metabolic enzymes active during this phase are potential targets for cancer chemotherapy.