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Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes

Macus Tien Kuo1, Niramol Savaraj, Lynn G Feun

  • 1Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, USA. tkuo@mdanderson.org

Oncotarget
|December 15, 2010
PubMed

Insights

Certain cancers like melanoma and HCC need external arginine (Arg) due to lacking argininosuccinate synthetase (ASS). Arginine-degrading enzyme ADI-PEG20 shows promise but resistance can occur, suggesting metabolic pathway modulation is key.

Area of Science:

  • Oncology
  • Biochemistry
  • Cancer Metabolism

Background:

  • Melanoma and hepatocellular carcinoma (HCC) are often auxotrophic for arginine (Arg) due to absent argininosuccinate synthetase (ASS).
  • These cancer cells rely on external Arg for survival and are vulnerable to Arg-depleting therapies.
  • Pegylated arginine deiminase (ADI-PEG20) is a promising agent for treating these cancers, inducing cell death via autophagy.

Purpose of the Study:

  • To investigate the mechanisms of ADI-PEG20 resistance in arginine auxotrophic cancers.
  • To explore the role of metabolic regulators HIF-1α and c-Myc in ADI-PEG20 efficacy.
  • To identify potential strategies for improving ADI-PEG20 treatment outcomes.

Main Methods:

  • Analysis of ASS expression in melanoma patients treated with ADI-PEG20.
  • Assessment of ADI-PEG20 effects on HIF-1α and c-Myc expression in cultured melanoma cells.
  • Investigation of the regulatory network involving c-Myc, Sp4, and HIF1α in ASS induction.

Main Results:

  • Re-expression of ASS is linked to ADI-PEG20 resistance in melanoma patients.
  • ADI-PEG20 down-regulates HIF-1α and up-regulates c-Myc in cultured melanoma cells.
  • c-Myc and Sp4 positively regulate ASS induction, while HIF1α negatively regulates it.

Conclusions:

  • Targeting cancer cell metabolism by modulating HIF-1α and c-Myc may enhance ADI-PEG20 efficacy.
  • Understanding the interplay between ASS, HIF-1α, and c-Myc is crucial for overcoming treatment resistance.
  • ADI-PEG20's mechanism involves complex metabolic reprogramming in arginine auxotrophic tumors.
Keywords:
ADI-PEG20arginasearginineauxotrophydrug resistancetargeted therapy

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