Arginine deiminase resistance in melanoma cells is associated with metabolic reprogramming, glucose dependence, and glutamine addiction
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Many malignant human tumors, including melanomas, are auxotrophic for arginine due to reduced expression of argininosuccinate synthetase-1 (ASS1), the rate-limiting enzyme for arginine biosynthesis. Pegylated arginine deiminase (ADI-PEG20), which degrades extracellular arginine, resulting in arginine deprivation, has shown favorable results in clinical trials for treating arginine-auxotrophic tumors. Drug resistance is the major obstacle for effective ADI-PEG20 usage. To elucidate mechanisms of resistance, we established several ADI-PEG20–resistant (ADIR) variants from A2058 and SK-Mel-2 melanoma cells. Compared with the parental lines, these ADIR variants showed the following characteristics: (i) all ADIR cell lines showed elevated ASS1 expression, resulting from the constitutive binding of the transcription factor c-Myc on the ASS1 promoter, suggesting that elevated ASS1 is the major mechanism of resistance; (ii) the ADIR cell lines exhibited enhanced AKT signaling and were preferentially sensitive to PI3K/AKT inhibitors, but reduced mTOR signaling, and were preferentially resistant to mTOR inhibitor; (iii) these variants showed enhanced expression of glucose transporter-1 and lactate dehydrogenase-A, reduced expression of pyruvate dehydrogenase, and elevated sensitivity to the glycolytic inhibitors 2-deoxy-glucose and 3-bromopyruvate, consistent with the enhanced glycolytic pathway (the Warburg effect); (iv) the resistant cells showed higher glutamine dehydrogenase and glutaminase expression and were preferentially vulnerable to glutamine inhibitors. We showed that c-Myc, not elevated ASS1 expression, is involved in upregulation of many of these enzymes because knockdown of c-Myc reduced their expression, whereas overexpressed ASS1 by transfection reduced their expression. This study identified multiple targets for overcoming ADI-PEG resistance in cancer chemotherapy using recombinant arginine-degrading enzymes. Mol Cancer Ther; 12(11); 2581–90. ©2013 AACR.
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The use of arginine-catabolizing enzymes may not be an effective therapeutic strategy for all ASS1-deficient cancers, as some ADI-treated tumors have been found to re-express ASS1.
“However, the use of arginine-catabolizing enzymes may not be an effective therapeutic strategy for all ASS1-deficient cancers, as some ADI-treated tumors have been found to re-express ASS1 (Feun et al., 2012; Long et al., 2013; Shen et al., 2003).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Long et al., 2013
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- Authors
- Long, Y., Tsai, W.-B., Wangpaichitr, M., Tsukamoto, T., Savaraj, N., Feun, L. G., & Kuo, M. T.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Kuo, Macus Tien
- Venue
- Molecular Cancer Therapeutics
- Published
- 2013-11-01
- Volume
- 12
- Issue
- 11
- Pages
- 2581-2590
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC3839414
- OpenAlex
- W2108745454
- Cited by
- 121
- References
- 48
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 5 · 2023: 6 · 2022: 11 · 2021: 20 · 2020: 6 · 2019: 11 · 2018: 10 · 2017: 8 · 2016: 12 · 2015: 11 · 2014: 3 · 2013: 1
- FWCI
- 7.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (IK2 BX001289)
- National Cancer Institute (R01CA149260, R0I-CA149260)
- National Institute of Neurological Disorders and Stroke (R21NS074151)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- ADI-PEG20, melanoma, arginine auxotrophy, argininosuccinate synthetase 1, c-Myc, Akt signaling, mTOR signaling, Warburg effect, glycolysis, glutamine addiction, glutaminase, drug resistance mechanisms
- MeSH terms
- Arginine, Argininosuccinate Synthase, Glucose, Glutamine, Humans, Hydrolases, Lipids, Melanoma, Polyethylene Glycols, Transfection, Signal Transduction, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Cell Line, Tumor, Gene Knockdown Techniques
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