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Cell Rep. 2019 Feb 12;26(7):1691-1700.e5. doi: 10.1016/j.celrep.2019.01.059.

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

Author information

1
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.
2
Departments of Medicine and Pharmacology, University of California, San Diego, 9500 Gilman Avenue, La Jolla, CA 92093, USA.
3
Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
4
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. Electronic address: roland.nilsson@ki.se.

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.

KEYWORDS:

ARG2; OAT; arginase 2; basal-like breast cancer; cancer metabolism; isotope tracing; mass spectrometry; ornithine; polyamines

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