Research shows urea cycle enzymes are repressed in kidney cancer
New research by the University of Pennsylvania now provides insights into the biology of kidney cancer. Existing therapies only benefit some of the patients with kidney cancer. The new research may lead to novel therapeutic strategies to treat the disease.
Kidney cancer, or renal cancer, is in the list of common cancer types that are diagnosed with the greatest frequency globally. Its incidence has been increasing over the past decade, and this is thought to correlate with the increasing incidence of obesity, which is a known risk factor for kidney cancer. Another reason for the increase in the incidence of kidney cancer may be the increasing use of imaging techniques such as CT that facilitate the detection and diagnosis of kidney cancer. A good news regarding kidney cancer is that it’s often diagnosed at earlier stages when the tumors are confined to the kidney and have not spread to distant organs. This makes treatment easier and prognosis better.
On the basis of the cell type that cancer develops from, kidney cancer can be divided into several different types. Renal cell carcinoma (RCC) arises from the tubules of the kidney, and about 90% of all kidney cancers can be attributed to RCC. Well-established risk factors for RCC include smoking, obesity, hypertension, and hepatitis C. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), accounting for 75% of all RCCs. The clear cell is so named because the cell shows a clear cytoplasm that reflects high lipid content. ccRCC is an aggressive and highly treatment-resistant tumor type that has a high risk of metastasis and a low survival rate.
In the new research, a team composed by scientists from the University of Pennsylvania and Sun Yat-Sen University investigated the biology of kidney cancer from many aspects, given that the etiology of kidney cancer is complex and involves multiple cellular abnormalities. Integrating metabolomics, genomic, and transcriptomic data, the team discovered that enzymes in multiple metabolic pathways are universally depleted in human ccRCC tumors. One of these enzymes, called arginase 2 (ARG2)
, is critical for the urea cycle. Reduced ARG2 activity was found to promote ccRCC tumor growth via multiple mechanisms. Another urea cycle enzyme, called argininosuccinate synthase 1 (ASS1)
, is also significantly repressed in ccRCC. Therefore, restoring the enzymes depleted in ccRCC tumors might have therapeutic effects.
Detailed in Cell Metabolism, the study titled "Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity" would facilitate the development of therapies for ccRCC.
The urea cycle is a series of biochemical reactions that help eliminate ammonia (a toxic by-product of protein metabolism) from the body. These reactions are catalyzed by several key enzymes, including ARG2 and ASS1. The deficiency of one or more of these enzymes can affect the normal function of the urea cycle. Urea cycle dysfunction leads to excess amount of ammonia in the body, which can lead to many health problems.