Eytan Ruppin co-authors research on Argininosuccinate deficient tumors

Descriptive image for Eytan Ruppin co-authors research on Argininosuccinate deficient tumors

On November 11th 2015, Eytan Ruppin, Professor of Computer Science, and Director of the Center for Bioinformatics and Computation Biology published a co-authored a paper entitled "Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis" in Nature.  The team of scientists examined two types citrullinaemia ( amino acid disorders that do not allow cells to produce citrin--which is essential to removing urea, ammonia, and other toxic substances from the blood via the liver) to show that levels of Argininosuccinate synthase (ASS1), the missing enzyme that contributes to one type of citrullinaemia (CTLN1 as opposed to CTLN2), is also 'silent' in cancers. Ruppin and his collaborators determined that the pathways to the disorders CTLN1 and CTLN2 have a different relationship with ASS1. After determining that CTLN2 had some commonality with the cancerous cells, the team demonstrated that along with other processes, blocking the citrin can keep cancerous cells from proliferating. They learned that by downregulating (or decreasing the quantity of) ASS1 in the cells, they have come up with a new way to treat the disease.

In order to determine this novel treatment, collaborators worked with The Cancer Genome Atlas Database, The TCGA database of tumours. 

The full summary is as follows:

"Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia1. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown2. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis."



The Department welcomes comments, suggestions and corrections.  Send email to editor [-at-] cs [dot] umd [dot] edu.