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

• Published in: Cell metabolism 2018-06, Vol.27 (6), p.1263-1280.e6
• Main Authors: Ochocki, Joshua D., Khare, Sanika, Hess, Markus, Ackerman, Daniel, Qiu, Bo, Daisak, Jennie I., Worth, Andrew J., Lin, Nan, Lee, Pearl, Xie, Hong, Li, Bo, Wubbenhorst, Bradley, Maguire, Tobi G., Nathanson, Katherine L., Alwine, James C., Blair, Ian A., Nissim, Itzhak, Keith, Brian, Simon, M. Celeste
• Format: Article
• Language: English
• Subjects: amino acids; Animals; Arginase - genetics; Arginase - metabolism; Argininosuccinate Synthase - metabolism; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - enzymology; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Gene Expression Profiling; Heterografts; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - enzymology; Kidney Neoplasms - pathology; metabolism; Mice; Mice, Nude; polyamines; Polyamines - metabolism; pyridoxal phosphate; Pyridoxal Phosphate - metabolism; renal cancer; Urea - metabolism; urea cycle
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2018.04.009

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. [Display omitted] •Multiple urea cycle enzymes are significantly underexpressed in ccRCC•ccRCC progression is dependent on alterations in ammonia metabolism•Reduced urea cycle activity conserves the biosynthetic cofactor pyridoxal-5′-phosphate•Polyamine accumulation represents a metabolic vulnerability for ccRCC Ochocki et al. show that clear cell renal cell carcinoma (ccRCC) tumors have altered ammonia metabolism with multiple urea cycle enzymes being significantly underexpressed. Loss of the urea cycle enzyme arginase2 (ARG2) promotes ccRCC tumor progression by conserving essential biosynthetic cofactor pools and preventing toxic polyamine build up.