The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells.
The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells.
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DOI：
10.18632/oncotarget.5308
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发表时间：
2015-10-27
期刊：
影响因子：
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通讯作者：
Sveinbjørnsson B
中科院分区：
文献类型：
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作者：
Eike LM;Yang N;Rekdal Ø;Sveinbjørnsson B
宿主防御肽（Host Defense Peptides，HDPs）是存在于大多数物种中的天然存在的分子，其中它们在抵抗入侵病原体的第一线防御中发挥重要作用，并且已经显示出若干HDPs具有抗癌活性。对HDP牛乳铁蛋白的构效关系研究揭示了具有溶瘤特性的九聚体肽LTX-315的从头设计。在本研究中，我们研究了LTX-315在人黑素瘤细胞（A375）中的溶瘤活性。LTX-315在2小时内诱导快速质膜破裂和细胞死亡。在低浓度下，荧光标记的LTX-315被内化并积累在线粒体附近的细胞质空泡中。LTX-315处理的结果显示线粒体膜电位降低，并且在超微结构水平上，线粒体形态显著改变。在肽处理后几分钟，危险信号（DAMP）如ATP、细胞色素C和HMGB 1释放到培养细胞的细胞上清液中是明显的。LTX-315的溶瘤作用涉及细胞膜和线粒体的扰动以及随后DAMP的释放，这可能突出了LTX-315诱导完全消退和长期保护性免疫应答的能力，如先前在实验动物模型中报道的。
Host defense peptides (HDPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line defense against intruding pathogens, and several HDPs have been shown to possess anticancer activity. Structure-activity relationship studies on the HDP bovine lactoferricin revealed a de novo design of a nonamer peptide LTX-315, with oncolytic properties. In the present study, we investigated the oncolytic activity of LTX-315 in human melanoma cells (A375). LTX-315 induced a rapid plasma membrane disruption and cell death within 2 hours. At a low concentration, fluorescence-labeled LTX-315 was internalized and accumulated in cytoplasmic vacuoles in close proximity to the mitochondria. The mitochondrial membrane potential was shown to depolarize as a consequence of LTX-315 treatment and at ultrastructural level, the mitochondria morphology was significantly altered. Release of danger signals (DAMPs) such as ATP, Cytochrome C and HMGB1 into the cell supernatant of cultured cells was evident minutes after peptide treatment. The oncolytic effect of LTX-315 involving perturbation of both the cell membrane and the mitochondria with subsequent release of DAMPs may highlight the ability of LTX-315 to induce complete regression and long-term protective immune responses as previously reported in experimental animal models.