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

Macus Tien Kuo, Niramol Savaraj, Lynn G Feun

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

It has been shown that a subset of human cancers, notably, melanoma and hepatocellular carcinoma (HCC) are auxotrophic for arginine (Arg), because they do not express argininosuccinate synthetase (ASS), the rate-limiting enzyme for the biosynthesis of arginine from citrulline. These ASS-negative cancer cells require Arg from extracellular sources for survival. When they are exposed to recombinant Arg-degrading enzymes, e.g. arginine deiminase (ADI) or arginase, they die because of Arg starvation; whereas normal cells which express ASS are able to survive. A pegylated ADI (ADI-PEG20) has been developed for clinical trials for advanced melanoma and HCC; and favorable results have been obtained. ADI-PEG20 treatment induces autophagy in auxotrophic cancer cells leading to cell death. Clinical studies in melanoma patients show that re-expression of ASS is associated with ADI-PEG20 resistance. ADI-PEG20 treatment down-regulates the expression of HIF-1α but up-regulates c-Myc in culture melanoma cells. Induction of ASS by ADI-PEG20 involves positive regulators c-Myc and Sp4 and negative regulator HIF1α. Since both HIF-1α and c-Myc play important roles in cancer cell energy metabolism, together these results suggest that targeted cancer cell metabolism through modulation of HIF-1α and c-Myc expression may improve the efficacy of ADI-PEG20 in treating Arg auxotrophic tumors.

Original languageEnglish
Pages (from-to)246-251
Number of pages6
JournalOncotarget
Volume1
Issue number4
StatePublished - Aug 1 2010
Externally publishedYes

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Argininosuccinate Synthase
Arginine
Drug Therapy
Enzymes
Melanoma
Neoplasms
Hepatocellular Carcinoma
Arginase
Citrulline
Autophagy
Starvation
arginine deiminase
Energy Metabolism
Cell Death
Up-Regulation
Down-Regulation
Cell Culture Techniques
Clinical Trials
Survival
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes. / Kuo, Macus Tien; Savaraj, Niramol; Feun, Lynn G.

In: Oncotarget, Vol. 1, No. 4, 01.08.2010, p. 246-251.

Research output: Contribution to journalArticle

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