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Arginine Deiminase Resistance in Melanoma Cells Is Associated with Metabolic Reprogramming, Glucose Dependence, and Glutamine Addiction
Open accessAbstract
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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“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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Metadata
- 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 › Bacterial Cancer Therapy
- 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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