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Πέμπτη 10 Μαΐου 2018

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

Publication date: Available online 10 May 2018
Source:Cell Metabolism
Author(s): 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
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.

Graphical abstract

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Teaser

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.


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