Arginine deiminase resistance in melanoma cells is associated with metabolic reprogramming, glucose dependence, and glutamine addiction

Yan Long, Wen Bin Tsai, Medhi Wangpaichitr, Takashi Tsukamoto, Niramol Savaraj, Lynn G Feun, Macus Tien Kuo

Research output: Contribution to journalArticle

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Abstract

Many malignant human tumors, including melanomas, are auxotrophic for arginine due to reducedexpression 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.

Original languageEnglish
Pages (from-to)2581-2590
Number of pages10
JournalMolecular Cancer Therapeutics
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2013

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Argininosuccinate Synthase
Glutamine
Melanoma
Arginine
Glucose
Neoplasms
Oxidoreductases
Enzymes
Glutaminase
Cell Line
Facilitative Glucose Transport Proteins
ADI PEG20
arginine deiminase
Pyruvic Acid
Phosphatidylinositol 3-Kinases
Drug Resistance
Transfection
Transcription Factors
Up-Regulation
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Arginine deiminase resistance in melanoma cells is associated with metabolic reprogramming, glucose dependence, and glutamine addiction. / Long, Yan; Tsai, Wen Bin; Wangpaichitr, Medhi; Tsukamoto, Takashi; Savaraj, Niramol; Feun, Lynn G; Kuo, Macus Tien.

In: Molecular Cancer Therapeutics, Vol. 12, No. 11, 01.11.2013, p. 2581-2590.

Research output: Contribution to journalArticle

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