Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity.
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.
['Ochocki|Joshua D|JD|', 'Khare|Sanika|S|', 'Hess|Markus|M|', 'Ackerman|Daniel|D|', 'Qiu|Bo|B|', 'Daisak|Jennie I|JI|', 'Worth|Andrew J|AJ|', 'Lin|Nan|N|', 'Lee|Pearl|P|', 'Xie|Hong|H|', 'Li|Bo|B|', 'Wubbenhorst|Bradley|B|', 'Maguire|Tobi G|TG|', 'Nathanson|Katherine L|KL|', 'Alwine|James C|JC|', 'Blair|Ian A|IA|', 'Nissim|Itzhak|I|', 'Keith|Brian|B|', 'Simon|M Celeste|MC|']
D000818:Animals D001119:Arginase D001124:Argininosuccinate Synthase D002292:Carcinoma, Renal Cell D045744:Cell Line, Tumor D020869:Gene Expression Profiling D064593:Heterografts D006801:Humans D007680:Kidney Neoplasms D051379:Mice D008819:Mice, Nude D011073:Polyamines D011732:Pyridoxal Phosphate D014508:Urea
pyridoxal phosphate polyamines metabolism urea cycle renal cancer amino acids