Mapping Metabolic Events in the Cancer Cell Cycle Reveals Arginine Catabolism in the Committed SG <sub>2</sub>M Phase

Abstract

Alterations in both cell cycle regulation and cellular metabolism are associated with cancer transformation, and enzymes active in the committed cell cycle phase could represent vulnerabilities of cancer cells. Here, we map metabolic events in the G1 and SG2M cell cycle 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 was active during SG2M in transformed but not in normal cells. An integrative data analysis implicated the arginase 2 (ARG2) enzyme as a potential mechanism. While cancer cells exclusively used ARG2, normal epithelial cells synthesized ornithine via ornithine aminotransferase (OAT). Knockdown of ARG2 markedly reduced cancer cell growth and caused G2M arrest, and did not induce compensation via OAT. In human tumors, ARG2 was highly expressed in specific tumor types, including basal-like breast tumors. This study sheds new light on the interplay between metabolism and the cell cycle, and identifies ARG2 as a potential metabolic target.