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

doi:10.1016/j.celrep.2019.01.059

Irena Roci, Jeramie D Watrous + Show 5 more

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https://doi.org/10.1016/j.celrep.2019.01.059

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Abstract

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.

Highlights

The cell cycle is of fundamental importance in cell biology and in biomedicine, as cancer, inflammation, and autoimmune disorders all involve cell proliferation
Cell Sorting Allows Metabolism Measurements in Pure G1 and SG2M Subpopulations To enable the study of metabolic events in the cell cycle, we sought a method for separating cells into the G1 and ‘‘committed’’ SG2M phases that is applicable to any cell type and has minimal disturbance on cellular metabolism
In this paper, we have presented a large-scale investigation of metabolic events in the ‘‘committed’’ SG2M phase of the cell cycle, using a combination of cell sorting with mass spectrometry-based isotope tracing

Summary

Introduction

The cell cycle is of fundamental importance in cell biology and in biomedicine, as cancer, inflammation, and autoimmune disorders all involve cell proliferation. Proliferating cells must synthesize a multitude of cellular components while simultaneously catabolizing nutrients to obtain energy, all while maintaining essential cell functions How cells orchestrate these complex metabolic processes while progressing through the cell cycle is still poorly understood. Most mammalian cells are difficult to synchronize (Cooper, 2004), and most data have been gathered from a few transformed cell lines that are amenable to synchronization, including HeLa and mouse 3T3 cells. This is problematic, since cell-cycle regulation clearly differs across cell types (Kung et al, 1990), and it is of particular interest to study differences between normal and transformed cells. Systematic studies of metabolic events in the cell cycle across multiple cell types, including normal cells, are needed

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