Abstract
BackgroundKidney 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.MethodsWe 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.ResultsWe 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.ConclusionsccRCC 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.
Highlights
Kidney cancer is a common adult malignancy in the USA
As shown previously [18], we ascertained that the genes encoding enzymes of the urea cycle are underexpressed in Clear cell renal cell carcinoma (ccRCC) tumors when compared to normal kidneys (Fig. 1A, B)
As the importance of repressing mitochondrial arginase 2 (ARG2) as a metabolic tumor suppressor in ccRCC [18] has been established, we focused on the cytosolic urea cycle enzymes argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL) that convert citrulline and aspartate to arginine and fumarate via argininosuccinate
Summary
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. Studying altered cancer cell metabolism is not limited to evaluating a single event; rather, it is akin to observing changes in a complex and wide network of genes, enzymes, metabolites, and microenvironments [3, 4]. With their consistent and extensive metabolic rewiring, clear cell renal cell carcinomas (ccRCCs) represent an excellent model system to study the altered metabolism in cancer [4,5,6,7,8,9]. HIFα activation enhances the transcription of genes involved in angiogenesis (VEGFA), glucose uptake (GLUT1), survival (survivin), migration and invasion (CXCR4), and proliferation (EGFR) [15, 16]
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