Potent antitumor activity of a glutamyltransferase-derived peptide via an activation of oncosis pathway.
Potent antitumor activity of a glutamyltransferase-derived peptide via an activation of oncosis pathway.
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谷氨酰转移酶衍生肽通过激活肿瘤途径具有有效的抗肿瘤活性
DOI：
10.1038/s41598-021-93055-5
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发表时间：
2021-08-13
影响因子：
4.6
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Fang C;Li W;Yin R;Zhu D;Liu X;Wu H;Wang Q;Wang W;Bai Q;Chen B;Yao X;Chen Y
肝细胞癌（HCC）尽管治疗手段不断改进，但其预后仍很差，死亡率高。精确治疗的挑战是由于几乎没有针对HCC的靶向治疗。最近的研究表明，代谢和循环肽作为内源性开关纠正异常的细胞可塑性。本研究对人脐血清中低分子组分的抗肿瘤活性进行了研究，通过肽组分析鉴定出一个高丰度的肽段VI-13，该肽段被认为是谷氨酰转移酶信号肽的一部分。我们对VI-13进行了四个取代基的修饰，得到了一个类似肽VI-17，以提高其溶解性。我们的分析表明，肽VI-17诱导快速的上下文依赖性细胞死亡，并表现出对肝癌细胞的更高的敏感性，这是由聚乙二醇衰减，但不是坏死抑制剂，如z-VAD-favor或necrostatin-1。在形态学上，VI-17诱导细胞肿胀、起泡和膜破裂，并将细胞ATP和LDH释放到细胞外介质中，这是肿瘤过程的标志。VI-17通过钙离子内流诱导细胞膜孔形成、α-微管蛋白降解。这些结果表明，新的肽VI-17在HCC细胞中诱导胀亡，这可以作为开发HCC治疗干预的有希望的线索。
Hepatocellular carcinoma (HCC) still presents poor prognosis with high mortality rate, despite of the improvement in the management. The challenge for precision treatment was due to the fact that little targeted therapeutics are available for HCC. Recent studies show that metabolic and circulating peptides serve as endogenous switches for correcting aberrant cellular plasticity. Here we explored the antitumor activity of low molecular components in human umbilical serum and identified a high abundance peptide VI-13 by peptidome analysis, which was recognized as the part of glutamyltransferase signal peptide. We modified VI-13 by inserting four arginines and obtained an analog peptide VI-17 to improve its solubility. Our analyses showed that the peptide VI-17 induced rapid context-dependent cell death, and exhibited a higher sensitivity on hepatoma cells, which is attenuated by polyethylene glycol but not necrotic inhibitors such as z-VAD-fmk or necrostatin-1. Morphologically, VI-17 induced cell swelling, blebbing and membrane rupture with release of cellular ATP and LDH into extracellular media, which is hallmark of oncotic process. Mechanistically, VI-17 induced cell membrane pore formation, degradation of α-tubulin via influx of calcium ion. These results indicated that the novel peptide VI-17 induced oncosis in HCC cells, which could serve as a promising lead for development of therapeutic intervention of HCC.
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影响因子：
81.5
作者：
Llovet, Josep M.;Zucman-Rossi, Jessica;Gores, Gregory
通讯作者：
Gores, Gregory
影响因子：
--
作者：
Eike LM;Yang N;Rekdal Ø;Sveinbjørnsson B
通讯作者：
Sveinbjørnsson B
影响因子：
64.8
作者：
Loose, Christopher;Jensen, Kyle;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
LRIF1 与 HP1α 相互作用，协调有丝分裂过程中准确的染色体分离
影响因子：
5.5
作者：
Akram, Saima;Yang, Fengrui;Liu, Xing
通讯作者：
Liu, Xing