Role of the cystathionine γ lyase/hydrogen sulfide pathway in human melanoma progression
Role of the cystathionine γ lyase/hydrogen sulfide pathway in human melanoma progression
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DOI：
10.1111/pcmr.12312
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发表时间：
2015-01-01
影响因子：
4.3
通讯作者：
Ianaro, Angela
中科院分区：
文献类型：
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作者：
Panza, Elisabetta;De Cicco, Paola;Ianaro, Angela
在人类中，两种主要的代谢酶合成硫化氢（H2S）：胱硫醚裂解酶（CSE）和胱硫醚合成酶（CBS）。第三种酶，3-巯基丙酮酸硫转移酶（3-MST），在底物3-巯基丙酮酸（3-MP）存在下合成H2S。对人黑色素瘤样品进行的免疫组织化学分析表明，CSE表达在原发性肿瘤中最高，在转移性病变中降低，在非淋巴结转移中几乎沉默。CSE的过度表达诱导人黑色素瘤细胞自发凋亡的发现证实了CSE发挥的主要作用。使用不同的H2S供体实现了相同的效果，其中最活跃的是二烯丙基三硫化物（DATS）。主要的促凋亡机制是抑制核因子-B的活性和抑制AKT和细胞外信号调节激酶途径。使用鼠黑素瘤模型在体内获得概念验证。事实上，无论是l-半胱氨酸，CSE底物，或DATS抑制小鼠肿瘤生长。总之，我们已经确定l-半胱氨酸/CSE/H2S途径参与黑色素瘤进展。
In humans, two main metabolic enzymes synthesize hydrogen sulfide (H2S): cystathionine lyase (CSE) and cystathionine synthase (CBS). A third enzyme, 3-mercaptopyruvate sulfurtransferase (3-MST), synthesizes H2S in the presence of the substrate 3-mercaptopyruvate (3-MP). The immunohistochemistry analysis performed on human melanoma samples demonstrated that CSE expression was highest in primary tumors, decreased in the metastatic lesions and was almost silent in non-lymph node metastases. The primary role played by CSE was confirmed by the finding that the overexpression of CSE induced spontaneous apoptosis of human melanoma cells. The same effect was achieved using different H2S donors, the most active of which was diallyl trisulfide (DATS). The main pro-apoptotic mechanisms involved were suppression of nuclear factor-B activity and inhibition of AKT and extracellular signal-regulated kinase pathways. A proof of concept was obtained in vivo using a murine melanoma model. In fact, either l-cysteine, the CSE substrate, or DATS inhibited tumor growth in mice. In conclusion, we have determined that the l-cysteine/CSE/H2S pathway is involved in melanoma progression.