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

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.

• Authors: Joshua D Ochocki, Sanika Khare, Markus Hess, Daniel Ackerman, Bo Qiu, Jennie I Daisak, Andrew J Worth, Nan Lin, Pearl Lee, Hong Xie, Bo Li, Bradley Wubbenhorst, Tobi G Maguire, Katherine L Nathanson, James C Alwine, Ian A Blair, Itzhak Nissim, Brian Keith, M Celeste Simon
• Journal: Cell metabolism (Cell Metab) Vol. 27 Issue 6 Pg. 1263-1280.e6 (Jun 05 2018) ISSN: 1932-7420 [Electronic] United States
• PMID: 29754953 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Polyamines
• Pyridoxal Phosphate
• Urea
• ARG2 protein, human
• Arginase
• Argininosuccinate Synthase

Topics

• Animals
• Arginase (genetics, metabolism)
• Argininosuccinate Synthase (metabolism)
• Carcinoma, Renal Cell (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Gene Expression Profiling
• Heterografts
• Humans
• Kidney Neoplasms (drug therapy, enzymology, pathology)
• Mice
• Mice, Nude
• Polyamines (metabolism)
• Pyridoxal Phosphate (metabolism)
• Urea (metabolism)