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.
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Authors | Macus Tien Kuo, Niramol Savaraj, Lynn G Feun |
Journal | Oncotarget
(Oncotarget)
Vol. 1
Issue 4
Pg. 246-51
(Aug 2010)
ISSN: 1949-2553 [Electronic] United States |
PMID | 21152246
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)
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Chemical References |
- Antineoplastic Agents
- HIF1A protein, human
- Hypoxia-Inducible Factor 1, alpha Subunit
- SP4 protein, human
- Sp4 Transcription Factor
- Polyethylene Glycols
- Arginine
- Hydrolases
- Arginase
- ADI PEG20
- arginine deiminase
- Argininosuccinate Synthase
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Topics |
- Antineoplastic Agents
(therapeutic use)
- Arginase
(metabolism)
- Arginine
(deficiency, metabolism)
- Argininosuccinate Synthase
(genetics, metabolism)
- Autophagy
(drug effects)
- Gene Expression Regulation, Neoplastic
- Genes, myc
- Humans
- Hydrolases
(pharmacology, therapeutic use)
- Hypoxia-Inducible Factor 1, alpha Subunit
(genetics, metabolism)
- Molecular Targeted Therapy
- Neoplasms
(drug therapy, metabolism)
- Polyethylene Glycols
(pharmacology, therapeutic use)
- Sp4 Transcription Factor
(genetics, metabolism)
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