Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase
Abstract
Recently, pegylated arginine deiminase (ADI; EC 3.5.3.6) has been used to treat the patients with hepatocellular carcinoma or melanoma, in which the level of argininosuccinate synthetase (ASS) activity is low or undetectable. The efficacy of its antitumor activity largely depends on the level of intracellular ASS, which enables tumor cells to recycle citrulline to arginine. Thus, we examined the expression levels of ASS in various cancer cells and found that it is low in renal cell carcinoma (RCC) cells, rendering the cells highly sensitive to arginine deprivation by ADI treatment. Immunohistochemical analysis revealed that in biopsy specimens from RCC patients (n = 98), the expression of ASS is highly demonstrated in the epithelium of normal proximal tubule but not seen in tumor cells. Furthermore, RCC cells treated with ADI showed remarkable growth retardation in a dose dependent manner. ADI also exerted in vivo antiproliferative effect on the allografted renal cell carcinoma (RENCA) tumor cells and prolonged the survival of tumor-bearing mice. Histological examination of the tumors revealed that tumor angiogenesis and vascular endothelial growth factor (VEGF) expression were significantly diminished by ADI administration. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of RCC in ways of inhibitions of arginine availability and neovascularization.
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ASS1 and ASL are frequently epigenetically silenced in melanoma, renal cell carcinoma, and hepatocellular carcinoma.
“Intriguingly, both ASS1 and ASL enzymes are frequently epigenetically silenced in melanoma, renal cell carcinoma and hepatocellular carcinoma (Bowles et al., 2008; Ensor et al., 2002; Yoon et al., 2007).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Yoon et al., 2007
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- Authors
- Yoon, C., Shim, Y., Kim, E., Lee, J., Won, N., Kim, J., Park, I., Yoon, D., & Min, B.
- Affiliations
- Korea University (KR)
- Seoul National University (KR)
- Inha University (KR)
- Corresponding author
- Min, Bon‐Hong
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2006-12-27
- Volume
- 120
- Issue
- 4
- Pages
- 897-905
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W1983116683
- Cited by
- 165
- References
- 37
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 9 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 9 · 2019: 9 · 2018: 9 · 2017: 11 · 2016: 8 · 2015: 7 · 2014: 10 · 2013: 8 · 2012: 10
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A050252)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Keywords
- renal cell carcinoma, argininosuccinate synthetase, arginine deiminase, arginine deprivation, tumor growth inhibition, tumor angiogenesis, vascular endothelial growth factor, neovascularization, proximal tubule, Renca cells, cancer therapy
- MeSH terms
- Adult, Aged, Animals, Arginase, Arginine, Argininosuccinate Synthase, Carcinoma, Renal Cell, Citrulline, Female, Humans, Hydrolases, Kidney Neoplasms, Male, Mice, Inbred BALB C, Middle Aged, Neovascularization, Pathologic, Polyethylene Glycols, Tumor Cells, Cultured, Survival Rate, Xenograft Model Antitumor Assays, Vascular Endothelial Growth Factor A, Cell Growth Processes, Mice
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