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Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity.
- Source :
-
Cell metabolism [Cell Metab] 2018 Jun 05; Vol. 27 (6), pp. 1263-1280.e6. Date of Electronic Publication: 2018 May 10. - Publication Year :
- 2018
-
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.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Arginase genetics
Argininosuccinate Synthase metabolism
Carcinoma, Renal Cell drug therapy
Carcinoma, Renal Cell enzymology
Cell Line, Tumor
Gene Expression Profiling
Heterografts
Humans
Kidney Neoplasms drug therapy
Kidney Neoplasms enzymology
Mice
Mice, Nude
Pyridoxal Phosphate metabolism
Urea metabolism
Arginase metabolism
Carcinoma, Renal Cell pathology
Kidney Neoplasms pathology
Polyamines metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-7420
- Volume :
- 27
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 29754953
- Full Text :
- https://doi.org/10.1016/j.cmet.2018.04.009