摘要
背景:当肿瘤对一系列不同的抗癌药物具有交叉抗性时,发生癌症中的多药耐药性(MDR)。可以获得MDR的一种机制是通过细胞与细胞的传播途径。膜衍生的微粒(MP)在这个过程中正在成为重要的信号分子。 MP从大多数真核细胞中释放,并将功能性蛋白质和核酸转移到受体细胞,从而赋予癌细胞群体内的有害性状,包括MDR,转移和血管生成。已知MP形成依赖于钙蛋白酶,细胞内半胱氨酸蛋白酶,其用于切割质膜下面的细胞骨架,导致细胞表面起泡 目的:建立钙蛋白酶在恶性和非恶性细胞囊泡中的作用,1)比较静息时的细胞膜渗透和细胞内钙的释放,以及2)在钙蛋白酶抑制剂II(ALLM)存在和不存在的情况下进行比较, 。 方法:本研究使用高分辨率原子力显微镜(AFM)检查恶性细胞与非恶性细胞之间的渗透性差异。分析HBEC,MBE-F,MCF-7和MCF-7 / Dx细胞,静置后用钙离子载体A23187处理18小时。钙激活和静息恶性和非恶性细胞的蒸煮也是在钙蛋白酶抑制剂II(ALLM)处理18小时后进行评估的。 结果:与非恶性人脑内皮细胞(HBEC)和人类乳腺上皮细胞(MBE-F)相比,我们证明恶性MCF-7和MCF-7 / Dx细胞在休息时具有本质上的更高程度的泡沫化。使用钙离子载体A23187的细胞活化导致所有细胞类型中的泡沫增加。我们显示,钙蛋白酶介导的MP生物发生是恶性细胞休息的主要途径,因为血浆蛋白酶抑制剂II(ALLM)显示出抑制作用。 结论:这些结果表明,恶性和非恶性细胞中存在生物传播途径的差异,并且在定义新的策略选择性靶向恶性细胞以规避通过细胞外囊泡细胞间交换获得的有害性状方面具有重要意义。
关键词: 原子力显微镜,乳腺癌,钙,钙蛋白酶,细胞外囊泡,微粒,多药耐药性,囊泡。
图形摘要
Current Cancer Drug Targets
Title:Calcium-calpain Dependent Pathways Regulate Vesiculation in Malignant Breast Cells
Volume: 17 Issue: 5
关键词: 原子力显微镜,乳腺癌,钙,钙蛋白酶,细胞外囊泡,微粒,多药耐药性,囊泡。
摘要: Background: Multidrug resistance in cancer (MDR) occurs when tumours become crossresistant to a range of different anticancer agents. One mechanism by which MDR can be acquired is through cell to cell communication pathways. Membrane-derived microparticles (MPs) are emerging as important signaling molecules in this process. MPs are released from most eukaryotic cells and transfer functional proteins and nucleic acids to recipient cells conferring deleterious traits within the cancer cell population including MDR, metastasis, and angiogenesis. MP formation is known to be dependent on calpain, an intracellular cysteine protease which acts to cleave the cytoskeleton underlying the plasma membrane, resulting in cellular surface blebbing
Objective: To establish the role of calpain in vesiculation in malignant and non-malignant cells by 1) comparing membrane vesiculation at rest and following the release of intracellular calcium, and 2) comparing vesiculation in the presence and absence of calpain inhibitor II (ALLM). Method: This study examines the differences in vesiculation between malignant and non-malignant cells using high-resolution Atomic Force Microscopy (AFM). HBEC, MBE-F, MCF-7, and MCF- 7/Dx cells were analysed at rest and following treatment with calcium ionophore A23187 for 18 hours. Vesiculation of calcium activated and resting malignant and non-malignant cells was also assessed after 18 hour treatment of calpain inhibitor II (ALLM). Results: We demonstrate that malignant MCF-7 and MCF-7/Dx cells have an intrinsically higher degree of vesiculation at rest when compared to non-malignant human brain endothelial cells (HBEC) and human mammary epithelial cells (MBE-F). Cellular activation with the calcium ionophore A23187 resulted in an increase in vesiculation in all cell types. We show that calpain-mediated MP biogenesis is the dominant pathway at rest in malignant cells as vesiculation was shown to be inhibited with calpain inhibitor II (ALLM). Conclusion: These results suggest that differences in the biogenic pathways exist in malignant and non-malignant cells and have important implications in defining novel strategies to selectively target malignant cells for the circumvention of deleterious traits acquired through intercellular exchange of extracellular vesicles.Export Options
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Cite this article as:
Calcium-calpain Dependent Pathways Regulate Vesiculation in Malignant Breast Cells, Current Cancer Drug Targets 2017; 17 (5) . https://dx.doi.org/10.2174/1568009616666161026165736
DOI https://dx.doi.org/10.2174/1568009616666161026165736 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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