title: Arginine deiminase resistance in melanoma cells is associated with metabolic reprogramming, glucose dependence, and glutamine addiction.
abstract: 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 (ADI(R)) variants from A2058 and SK-Mel-2 melanoma cells. Compared with the parental lines, these ADI(R) variants showed the following characteristics: (i) all ADI(R) 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 ADI(R) 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.
authors: Corresponding Author: Macus Tien Kuo, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 951, Houston, TX 77030. tkuo@mdanderson.org.
authors: Yan
authors: Y
authors: Long
authors: Wen-Bin
authors: WB
authors: Tsai
authors: Medhi
authors: M
authors: Wangpaichitr
authors: Takashi
authors: T
authors: Tsukamoto
authors: Niramol
authors: N
authors: Savaraj
authors: Lynn G
authors: LG
authors: Feun
authors: Macus Tien
authors: MT
authors: Kuo
mesh_terms: D001120:Arginine / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology*; D008055:Lipids / Q000096:biosynthesis; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: D008055:Lipids; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine; D011092:Polyethylene Glycols; D001120:Arginine; D019869:Phosphatidylinositol 3-Kinases; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase; D005947:Glucose
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