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The Relationship of Arginine Deprivation, Argininosuccinate Synthetase and Cell Death in Melanoma

机译：黑色素瘤中精氨酸缺乏，精氨酸琥珀酸合成酶与细胞死亡的关系

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It has been shown that melanoma cells do not express argininosuccinate synthetase (ASS) and therefore are unable to synthesize arginine from citrulline. Depleting arginine using pegylated arginine deiminase (ADI-PEG20) results in cell death in melanoma but not normal cells. This concept was translated into clinical trial and responses were seen. However, induction of ASS expression does occur which results in resistance to ADI -PEG20. We have used 4 melanoma cell lines to study factors which may govern ASS expression. Although these 4 melanoma cell lines do not express ASS protein or mRNA as detected by both immunoblot and northernblot analysis, ASS protein can be induced after these cells are grown in the presence of ADI-PEG20, but again repressed after replenishing arginine in the media. The levels of induction are different and one cell line could not be induced. Interestingly, a melanoma cell line with the highest level of induction could also be made resistant to ADI-PEG20. This resistant line possesses high levels of ASS mRNA and protein expression which cannot be repressed with arginine. Our study indicates that ASS expression in melanoma cells is complex and governed by biochemical parameters which are different among melanoma cells.
机译：已经表明，黑色素瘤细胞不表达精氨酸琥珀酸酯合成酶（ASS），因此不能从瓜氨酸合成精氨酸。使用聚乙二醇化的精氨酸脱亚氨酶（ADI-PEG20）消耗精氨酸会导致黑色素瘤细胞死亡，但不会导致正常细胞死亡。这个概念被转化为临床试验，并看到了反应。但是，确实发生了ASS表达的诱导，这导致了对ADI -PEG20的抗性。我们已经使用了4种黑色素瘤细胞系来研究可能控制ASS表达的因子。尽管通过免疫印迹法和RNA印迹分析均检测到这四种黑素瘤细胞系均不表达ASS蛋白或mRNA，但是在这些细胞在ADI-PEG20存在下生长后可以诱导ASS蛋白，但是在培养基中补充精氨酸后再次被抑制。诱导水平不同，不能诱导一种细胞系。有趣的是，也可以使具有最高诱导水平的黑素瘤细胞系对ADI-PEG20具有抗性。该抗性品系具有无法被精氨酸抑制的高水平ASS mRNA和蛋白质表达。我们的研究表明，黑色素瘤细胞中ASS的表达是复杂的，并且受黑色素瘤细胞之间不同的生化参数的控制。

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