Arginine Deprivation, Autophagy, Apoptosis (AAA) for the Treatment of Melanoma

Title: Arginine Deprivation, Autophagy, Apoptosis (AAA) for the Treatment of Melanoma

Volume: 10 Issue: 4

Author(s): N. Savaraj, M. You, C. Wu, M. Wangpaichitr, M.T. Kuo and L.G. Feun

Affiliation:

Keywords: Arginine deiminase, argininosuccinate synthetase, melanoma

Abstract: The majority of melanoma cells do not express argininosuccinate synthetase (ASS), and hence cannot synthesize arginine from citrulline. Their growth and proliferation depend on exogenous supply of arginine. Arginine degradation using arginine deiminase (ADI) leads to growth inhibition and eventually cell death while normal cells which express ASS can survive. This notion has been translated into clinical trial. Pegylated ADI (ADI-PEG20) has shown antitumor activity in melanoma. However, the sensitivity to ADI is different among ASS(-) melanoma cells. We have investigated and reviewed the signaling pathways which are affected by arginine deprivation and their consequences which lead to cell death. We have found that arginine deprivation inhibits mTOR signaling but leads to activation of MEK and ERK with no changes in BRAF. These changes most likely lead to autophagy, a possible mechanism to survive by recycling intracellular arginine. However apoptosis does occur which can be both caspase-dependent or independent. In order to increase the therapeutic efficacy of this form of treatment, one should consider adding other agent(s) which can drive the cells toward apoptosis or inhibit the autophagic process.

Cite this article as:

Savaraj N., You M., Wu C., Wangpaichitr M., Kuo M.T. and Feun L.G., Arginine Deprivation, Autophagy, Apoptosis (AAA) for the Treatment of Melanoma, Current Molecular Medicine 2010; 10(4) . https://dx.doi.org/10.2174/156652410791316995