There has been renewed interest in amino acid deprivation to treat various human cancers. Certain tumors do not express argininosuccinate synthetase (ASS) and therefore are unable to synthesize arginine from citrulline. These tumors are auxotrophic for arginine and may be inhibited by arginine deprivation. Arginine deprivation can affect growth and apoptotic signaling. In addition, mTOR signaling and RAF/MEK/ERK1/2 signaling are also affected by arginine deprivation. Upon arginine deprivation, tumor cells undergo autophagy as a survival mechanism, but prolonged autophagy can lead to apoptotic cell death. Arginine derivation using pegylated arginine deiminase (ADI-PEG20) has been shown to have activity in malignant melanoma and hepatocellular carcinoma with minimal side effects. Why ASS is silent in certain tumor types is not known. Aberrant DNA methylation which leads to epigenetic silencing has been reported. Reexpression of ASS may lead to resistance to arginine deprivation treatment. Thus, understanding how the ASS gene is regulated is very important for this modality of cancer treatment.
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