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Cell Metab. 2018 Jun 5;27(6):1263-1280.e6. doi: 10.1016/j.cmet.2018.04.009. Epub 2018 May 10.

Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity.

Author information

1
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Program in Cancer Biology, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
4
Department of Medicine, Division of Translational Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Division of Genetics and Metabolism, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Biochemistry, and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: celeste2@pennmedicine.upenn.edu.

Abstract

Kidney cancer, one of the ten most prevalent malignancies in the world, has exhibited increased incidence over the last decade. The most common subtype is "clear cell" renal cell carcinoma (ccRCC), which features consistent metabolic abnormalities, such as highly elevated glycogen and lipid deposition. By integrating metabolomics, genomic, and transcriptomic data, we determined that enzymes in multiple metabolic pathways are universally depleted in human ccRCC tumors, which are otherwise genetically heterogeneous. Notably, the expression of key urea cycle enzymes, including arginase 2 (ARG2) and argininosuccinate synthase 1 (ASS1), is strongly repressed in ccRCC. Reduced ARG2 activity promotes ccRCC tumor growth through at least two distinct mechanisms: conserving the critical biosynthetic cofactor pyridoxal phosphate and avoiding toxic polyamine accumulation. Pharmacological approaches to restore urea cycle enzyme expression would greatly expand treatment strategies for ccRCC patients, where current therapies only benefit a subset of those afflicted with renal cancer.

KEYWORDS:

amino acids; metabolism; polyamines; pyridoxal phosphate; renal cancer; urea cycle

PMID:
29754953
PMCID:
PMC5990482
[Available on 2019-06-05]
DOI:
10.1016/j.cmet.2018.04.009

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