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

35 Pages Posted: 26 Sep 2018 Publication Status: Published

See all articles by Irena Roci

Irena Roci

Karolinska Institutet - Cardiovascular Medicine Unit

Jeramie D. Watrous

University of California, San Diego (UCSD) - Department of Pathology

Kim A. Lagerborg

University of California, San Diego (UCSD) - Department of Medicine

Lorenzo Lafranchi

Karolinska Institutet - Department of Cell and Molecular Biology

Arne Lindqvist

Karolinska Institutet - Department of Cell and Molecular Biology

Mohit Jain

University of California, San Diego (UCSD) - Department of Pathology

Roland Nilsson

Karolinska Institutet - Cardiovascular Medicine Unit

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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.

Suggested Citation

Roci, Irena and Watrous, Jeramie D. and Lagerborg, Kim A. and Lafranchi, Lorenzo and Lindqvist, Arne and Jain, Mohit and Nilsson, Roland, Mapping Metabolic Events in the Cancer Cell Cycle Reveals Arginine Catabolism in the Committed SG 2M Phase (September 26, 2018). Available at SSRN: https://ssrn.com/abstract=3255558 or http://dx.doi.org/10.2139/ssrn.3255558
This version of the paper has not been formally peer reviewed.

Irena Roci

Karolinska Institutet - Cardiovascular Medicine Unit

Stockholm, SE-171 77
Sweden

Jeramie D. Watrous

University of California, San Diego (UCSD) - Department of Pathology

9500 Gilman Drive
La Jolla, CA 92093-0636
United States

Kim A. Lagerborg

University of California, San Diego (UCSD) - Department of Medicine

9500 Gilman Drive
La Jolla, CA 92093
United States

Lorenzo Lafranchi

Karolinska Institutet - Department of Cell and Molecular Biology

Granits väg 4
SE-171 77 Stockholm, Stockholm 17171
Sweden

Arne Lindqvist

Karolinska Institutet - Department of Cell and Molecular Biology

Granits väg 4
SE-171 77 Stockholm, Stockholm 17171
Sweden

Mohit Jain

University of California, San Diego (UCSD) - Department of Pathology

9500 Gilman Drive
La Jolla, CA 92093-0636
United States

Roland Nilsson (Contact Author)

Karolinska Institutet - Cardiovascular Medicine Unit ( email )

Stockholm, SE-171 77
Sweden

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