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

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.

Keywords: ADI-PEG20; arginase; arginine; auxotrophy; drug resistance; targeted therapy.

Figure 1:. Metabolic pathways relevant to Arg deprivation strategy using ADI-PEG20

Shown in the center are the coupled TCA and urea cycles. In the urea cycle, arginine is metabolized by arginase to citrulline and urea. Arginine can be metabolized into citrulline and nitric oxide (NO) by nitroxide synthetase (NOS). Citrulline is converted into argininosuccinate (AS) by argininosuccinate synthetase (ASS). AS is recycled back to arginine by argininosuccinate lyase. In most melanoma cells, AS is not active, therefore, arginine must come from an external source. Treating melanoma cells with arginine deiminase (ADI), which converts arginine to citrulline and ammonia, results in arginine deprivation, leading to cell death in melanoma cells. We found that ASS expression can be induced in some melanoma cells involving the interplay of c-Myc/HIF-1α/Sp4. The relationships of this metabolic wiring and the function of HIF-1α and c-Myc are also indicated.