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首页> 外文期刊>Pigment cell research >Cysteine but not GSH Modulates the Radiosensitivity of Human Melanoma Cells by Affecting Both Survival and DNA Damage
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Cysteine but not GSH Modulates the Radiosensitivity of Human Melanoma Cells by Affecting Both Survival and DNA Damage

机译：半胱氨酸而不是谷胱甘肽通过影响生存和DNA损伤来调节人类黑色素瘤细胞的放射敏感性。

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Glutathione and its precursor cysteine are both known to react within any cells with oxidative species and thus play an important role in cellular defense mechanisms against oxidative stress. In melanocytes, these are also important precursors of melanogenesis by reacting non-enzymatically with L-dopaquinone to form the sulfur-containing pheomelanin. Our aim was to assess pigment role in the cellular radioprotection mechanism using a human melanoma cell model of mixed-type melanin under GSH depletion to obtain a radiosensitizing effect. The latter has been achieved either by cysteine (Cys) deprivation or glutathione (GSH) specific depletion. We first compared cell survival of Cys-deprived and glutathione (GSH)-depleted cells versus control cells. Cys deprivation was achieved by decreasing Cys concentration in the culture medium for 24 hr. In this condition, no toxicity was observed, Cys and GSH levels decreased, melanogenesis switched to a higher eumelanin synthesis and cells were significantly more resistant to 10-Gy dose of ionizing radiations than untreated cells. Glutathione depletion was achieved with the g-glutamylcysteine synthetase inhibitor buthionine-S-sulfoximine (BSO) for 24 hr at 50 μM, a concentration yielding no toxicity. In this condition, intracellular GSH level decreased but no change in pigmentation was observed and cells were slightly but significantly more sensitive to radiation than the control. We then compared DNA radio-induced damages by Comet assay in control cells, cells treated as above and cells with stimulated pigmentation by increasing Tyr concentration in the medium. Our results showed that, when intracellular eumelanin content increased, DNA damage decreased. By contrast, DNA damage increased in cells treated with BSO alone. It is concluded that increasing the intracellular eumelanin content by the melanin precursor Tyr or by favoring the Pheo- to Eumelanin switch, compensates for the loss of the two intracellular radioprotectors that are glutathione and cysteine.
机译：已知谷胱甘肽及其前体半胱氨酸都可以在任何细胞内与氧化性物质发生反应，因此在抵抗氧化应激的细胞防御机制中起着重要的作用。在黑素细胞中，它们也是黑素生成的重要前体，通过与L-多巴醌非酶反应形成含硫的酞菁。我们的目的是使用GSH耗竭下的混合型黑色素人类黑色素瘤细胞模型评估色素在细胞放射防护机制中的作用，从而获得放射增敏作用。后者可以通过半胱氨酸（Cys）剥夺或谷胱甘肽（GSH）特异性消耗来实现。我们首先比较了缺少Cys和谷胱甘肽（GSH）的细胞与对照细胞的细胞存活率。通过降低培养基中Cys浓度24小时来实现Cys剥夺。在这种情况下，未观察到毒性，Cys和GSH水平降低，黑色素生成转换为更高的双榄合成，并且细胞对10-Gy剂量电离辐射的抵抗力明显高于未处理的细胞。使用g-谷氨酰半胱氨酸合成酶抑制剂butionionine-S-sulfoximine（BSO）在50μM浓度下完成了24小时的谷胱甘肽消耗试验，该浓度不产生毒性。在这种情况下，细胞内GSH水平下降，但未观察到色素沉着变化，并且细胞对辐射的敏感性比对照略高，但明显更高。然后，我们通过彗星分析比较了对照细胞，按上述方法处理的细胞和通过增加培养基中Tyr浓度刺激色素沉着的细胞的DNA放射性诱导的损伤。我们的结果表明，当细胞内直链淀粉含量增加时，DNA损伤减少。相反，单独用BSO处理的细胞中DNA损伤增加。结论是，通过黑色素前体Tyr或通过促进Pheo- Eumelanin转换来增加细胞内Eumelanin的含量，可以补偿谷胱甘肽和半胱氨酸这两种细胞内放射防护剂的损失。

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