Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase
Open accessAbstract
Eukaryotic cells can synthesize the non-essential amino acid arginine from aspartate and citrulline using the enzyme argininosuccinate synthetase (ASS). It has been observed that ASS is underexpressed in various types of cancers ASS, for which arginine become auxotrophic. Arginine deiminase (ADI) is a prokaryotic enzyme that metabolizes arginine to citrulline and has been found to inhibit melanoma and hepatoma cancer cells deficient of ASS. We tested the hypothesis that pancreatic cancers have low ASS expression and therefore arginine deprivation by ADI will inhibit cell growth. ASS expression was examined in 47 malignant and 20 non-neoplastic pancreatic tissues as well as a panel of human pancreatic cancer cell lines. Arginine deprivation was achieved by treatment with a recombinant form of ADI formulated with polyethylene glycol (PEG-ADI). Effects on caspase activation, cell growth and cell death were examined. Furthermore, the effect of PEG-ADI on the in vivo growth of pancreatic xenografts was examined. Eighty-seven percent of the tumors lacked ASS expression; 5 of 7 cell lines similarly lacked ASS expression. PEG-ADI specifically inhibited growth of those cell lines lacking ASS. PEG-ADI treatment induced caspase activation and induction of apoptosis. PEG-ADI was well tolerated in mice despite complete elimination of plasma arginine; tumor growth was inhibited by approximately 50%. Reduced expression of ASS occurs in pancreatic cancer and predicts sensitivity to arginine deprivation achieved by PEG-ADI treatment. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of pancreatic cancer, a malignancy in which new therapy is desperately needed.
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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 Bowles et al., 2008
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- Authors
- Bowles, T. L., Kim, R., Galante, J., Parsons, C. M., Virudachalam, S., Kung, H., & Bold, R. J.
- Affiliations
- University of California Davis Medical Center (US)
- Corresponding author
- Bold, Richard J.
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2008-08-13
- Volume
- 123
- Issue
- 8
- Pages
- 1950-1955
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- PMC
- PMC4294549
- OpenAlex
- W2119097025
- Cited by
- 153
- References
- 44
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 7 · 2023: 13 · 2022: 8 · 2021: 15 · 2020: 9 · 2019: 11 · 2018: 8 · 2017: 11 · 2016: 11 · 2015: 6 · 2014: 14 · 2013: 4 · 2012: 3
- FWCI
- 6.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA093373)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK052659)
- 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 › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- pancreatic cancer, argininosuccinate synthetase, arginine deprivation, arginine deiminase, arginine auxotrophy, apoptosis, caspase activation, tumor xenografts, arginine metabolism, cancer cell lines
- MeSH terms
- Animals, Arginine, Argininosuccinate Synthase, Humans, Hydrolases, Immunohistochemistry, Mice, Nude, Pancreatic Neoplasms, Polyethylene Glycols, RNA, Messenger, Apoptosis, Xenograft Model Antitumor Assays, Cell Growth Processes, Mice
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