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

Cell Metabolism
Joshua D OchockiM Celeste Simon

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.

Citations

Apr 16, 2019·Expert Review of Molecular Diagnostics·Giuseppe LucarelliMichele Battaglia
May 26, 2018·Nature Reviews. Nephrology·Ellen F Carney
Oct 16, 2018·BioMed Research International·Jia YouYueyong Zhu
Dec 4, 2019·Annals of the New York Academy of Sciences·Jennifer CableWilliam Kaelin
Aug 30, 2018·Disease Models & Mechanisms·Almut Schulze, Mariia Yuneva
Sep 9, 2018·Nature Reviews. Cancer·Rom KeshetAyelet Erez
Jul 22, 2018·Science·Danielle J Sanchez, M Celeste Simon
Jun 7, 2019·Cancers·Alex J BottWei-Xing Zong
May 31, 2019·Nature·Miriam WaldenElton Zeqiraj
Jun 6, 2020·Frontiers in Immunology·Tomasz M GrzywaJakub Golab
Mar 30, 2019·Frontiers in Nutrition·Bruno Ramos-MolinaRafael Peñafiel
Oct 22, 2020·Journal of Clinical Medicine·Mohamed E AhmedPhilippe E Spiess
Jun 4, 2019·Molecular Cancer Research : MCR·Ankita BansalM Celeste Simon
Apr 17, 2021·Molecular & Cellular Oncology·Maria F Czyzyk-KrzeskaJohn T Cunningham
Jun 3, 2021·Medical Sciences : Open Access Journal·Shima Nakanishi, John L Cleveland
Jul 9, 2020·Developmental Cell·Fuming Li, M Celeste Simon
Jul 7, 2021·The FEBS Journal·Peter F DoubledayNeil L Kelleher
Mar 21, 2019·ACS Chemical Biology·Andrew ChoKayvan R Keshari
Sep 2, 2021·Molecular Cell·Emma HajajAyelet Erez
Jul 11, 2021·Cancer Discovery·Romain RiscalM Celeste Simon

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