ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism

Abstract Background Kidney cancer is a common adult malignancy in the USA. Clear cell renal cell carcinoma (ccRCC), the predominant subtype of kidney cancer, is characterized by widespread metabolic changes. Urea metabolism is one such altered pathway in ccRCC. The aim of this study was to elucidate...

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Autores principales:	Sanika Khare, Laura C. Kim, Graham Lobel, Paschalis-Thomas Doulias, Harry Ischiropoulos, Itzhak Nissim, Brian Keith, M. Celeste Simon
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	ccRCC Urea cycle Argininosuccinate synthase 1 Argininosuccinate lyase Aspartate DNA synthesis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c58358261d474004af1c1f7c4c61d199
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spelling	oai:doaj.org-article:c58358261d474004af1c1f7c4c61d1992021-12-05T12:23:14ZASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism10.1186/s40170-021-00271-82049-3002https://doaj.org/article/c58358261d474004af1c1f7c4c61d1992021-12-01T00:00:00Zhttps://doi.org/10.1186/s40170-021-00271-8https://doaj.org/toc/2049-3002Abstract Background Kidney cancer is a common adult malignancy in the USA. Clear cell renal cell carcinoma (ccRCC), the predominant subtype of kidney cancer, is characterized by widespread metabolic changes. Urea metabolism is one such altered pathway in ccRCC. The aim of this study was to elucidate the contributions of urea cycle enzymes, argininosuccinate synthase 1 (ASS1), and argininosuccinate lyase (ASL) towards ccRCC progression. Methods We employed a combination of computational, genetic, and metabolomic tools along with in vivo animal models to establish a tumor-suppressive role for ASS1 and ASL in ccRCC. Results We show that the mRNA and protein expression of urea cycle enzymes ASS1 and ASL are reduced in ccRCC tumors when compared to the normal kidney. Furthermore, the loss of ASL in HK-2 cells (immortalized renal epithelial cells) promotes growth in 2D and 3D growth assays, while combined re-expression of ASS1 and ASL in ccRCC cell lines suppresses growth in 2D, 3D, and in vivo xenograft models. We establish that this suppression is dependent on their enzymatic activity. Finally, we demonstrate that conservation of cellular aspartate, regulation of nitric oxide synthesis, and pyrimidine production play pivotal roles in ASS1+ASL-mediated growth suppression in ccRCC. Conclusions ccRCC tumors downregulate the components of the urea cycle including the enzymes argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). These cytosolic enzymes lie at a critical metabolic hub in the cell and are involved in aspartate catabolism and arginine and nitric oxide biosynthesis. Loss of ASS1 and ASL helps cells redirect aspartate towards pyrimidine synthesis and support enhanced proliferation. Additionally, reduced levels of ASS1 and ASL might help regulate nitric oxide (NO) generation and mitigate its cytotoxic effects. Overall, our work adds to the understanding of urea cycle enzymes in a context-independent of ureagenesis, their role in ccRCC progression, and uncovers novel potential metabolic vulnerabilities in ccRCC.Sanika KhareLaura C. KimGraham LobelPaschalis-Thomas DouliasHarry IschiropoulosItzhak NissimBrian KeithM. Celeste SimonBMCarticleccRCCUrea cycleArgininosuccinate synthase 1Argininosuccinate lyaseAspartateDNA synthesisNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancer & Metabolism, Vol 9, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ccRCC Urea cycle Argininosuccinate synthase 1 Argininosuccinate lyase Aspartate DNA synthesis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	ccRCC Urea cycle Argininosuccinate synthase 1 Argininosuccinate lyase Aspartate DNA synthesis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Sanika Khare Laura C. Kim Graham Lobel Paschalis-Thomas Doulias Harry Ischiropoulos Itzhak Nissim Brian Keith M. Celeste Simon ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism
description	Abstract Background Kidney cancer is a common adult malignancy in the USA. Clear cell renal cell carcinoma (ccRCC), the predominant subtype of kidney cancer, is characterized by widespread metabolic changes. Urea metabolism is one such altered pathway in ccRCC. The aim of this study was to elucidate the contributions of urea cycle enzymes, argininosuccinate synthase 1 (ASS1), and argininosuccinate lyase (ASL) towards ccRCC progression. Methods We employed a combination of computational, genetic, and metabolomic tools along with in vivo animal models to establish a tumor-suppressive role for ASS1 and ASL in ccRCC. Results We show that the mRNA and protein expression of urea cycle enzymes ASS1 and ASL are reduced in ccRCC tumors when compared to the normal kidney. Furthermore, the loss of ASL in HK-2 cells (immortalized renal epithelial cells) promotes growth in 2D and 3D growth assays, while combined re-expression of ASS1 and ASL in ccRCC cell lines suppresses growth in 2D, 3D, and in vivo xenograft models. We establish that this suppression is dependent on their enzymatic activity. Finally, we demonstrate that conservation of cellular aspartate, regulation of nitric oxide synthesis, and pyrimidine production play pivotal roles in ASS1+ASL-mediated growth suppression in ccRCC. Conclusions ccRCC tumors downregulate the components of the urea cycle including the enzymes argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). These cytosolic enzymes lie at a critical metabolic hub in the cell and are involved in aspartate catabolism and arginine and nitric oxide biosynthesis. Loss of ASS1 and ASL helps cells redirect aspartate towards pyrimidine synthesis and support enhanced proliferation. Additionally, reduced levels of ASS1 and ASL might help regulate nitric oxide (NO) generation and mitigate its cytotoxic effects. Overall, our work adds to the understanding of urea cycle enzymes in a context-independent of ureagenesis, their role in ccRCC progression, and uncovers novel potential metabolic vulnerabilities in ccRCC.
format	article
author	Sanika Khare Laura C. Kim Graham Lobel Paschalis-Thomas Doulias Harry Ischiropoulos Itzhak Nissim Brian Keith M. Celeste Simon
author_facet	Sanika Khare Laura C. Kim Graham Lobel Paschalis-Thomas Doulias Harry Ischiropoulos Itzhak Nissim Brian Keith M. Celeste Simon
author_sort	Sanika Khare
title	ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism
title_short	ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism
title_full	ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism
title_fullStr	ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism
title_full_unstemmed	ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism
title_sort	ass1 and asl suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism
publisher	BMC
publishDate	2021
url	https://doaj.org/article/c58358261d474004af1c1f7c4c61d199
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ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism

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