VA Medical Center, Miami, FL 33125, USA.
Curr Mol Med. 2010 Jun;10(4):405-12. doi: 10.2174/156652410791316995.
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 cell 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.
大多数黑色素瘤细胞不表达精氨酸合成酶（ASS），因此不能将瓜氨酸合成精氨酸。它们的生长和增殖依赖于精氨酸的外源性供应。使用精氨酸脱亚氨酶（ADI）降解精氨酸会导致生长抑制，最终导致细胞死亡，而表达 ASS 的正常细胞则可以存活。这一概念已转化为临床试验。聚乙二醇化 ADI（ADI-PEG20）已显示出对黑色素瘤的抗肿瘤活性。然而，ASS(-)黑色素瘤细胞对 ADI 的敏感性不同。我们已经研究并回顾了受精氨酸剥夺影响的信号通路及其导致细胞死亡的后果。我们发现，精氨酸剥夺抑制 mTOR 信号，但导致 MEK 和 ERK 激活，而 BRAF 没有变化。这些变化很可能导致自噬，这是一种通过回收细胞内精氨酸来存活的可能机制。然而，细胞凋亡确实会发生，既可以是 caspase 依赖性的，也可以是 caspase 非依赖性的。为了提高这种治疗形式的治疗效果，应该考虑添加其他药物，这些药物可以促使细胞向细胞凋亡或抑制自噬过程。
