抗肿瘤药物诱导肿瘤细胞凋亡机制的研究进展

综述了近年来抗肿瘤药物诱导肿瘤细胞凋亡作用机制的研究进展.抗肿瘤药物诱导肿瘤细胞凋亡的作用机制主要有：阻滞肿瘤细胞增殖周期、影响细胞凋亡信号的转导途径、调控癌基因和抑癌基因的表达、降低端粒酶的活性、激活活性氧途径、线粒体途径及调节细胞内pH诱导凋亡等.     

线粒体外膜通道蛋白VDAC与靶向肿瘤细胞凋亡

VDAC(Voltage-dependent anion channel)是位于线粒体外膜上的一种主要通道蛋白,参与线粒体内外物质和能量的运输,在线粒体与细胞其它部位的通讯中起重要调节作用.近年来研究发现,VDAC也是线粒体与其它蛋白质相互作用的功能结合位点,可与多种凋亡调节蛋白(如HK-Ⅰ/Ⅱ、Bcl-2家族蛋白、tubulin、MAP2/4等)以及非蛋白调节因子相互作用,参与调控细胞凋亡.因此,VDAC成为线粒体凋亡通路中一种关键的靶蛋白.本文对近年来VDAC在肿瘤细胞凋亡中的作用机制进行简要综述.     

三苯基膦盐在肿瘤诊断和治疗中的应用

针对靶向亚细胞器的治疗是肿瘤治疗的一个新兴研究方向,其机理是通过损伤亚细胞器或影响亚细胞器周围的环境,使细胞凋亡. 而在众多的亚细胞器中,线粒体是亚细胞的能量工厂,可以为亚细胞的各项生命活动提供能量,因此靶向线粒体治疗是亚细胞器治疗的热点之一. 此外,线粒体还参与细胞分化、细胞信息传递和细胞凋亡等过程. 诱导线粒体损伤或者影响线粒体内表达物质的正常供应关系,对亚细胞生存状态有巨大的影响. 三苯基膦（TPP）盐可以利用线粒体膜电位差来实现线粒体靶向功能,是最广为接受和应用较多的线粒体靶向小分子. 为了进一步增加其功能的多样性,往往会在TPP烷基链的尾端进行设计,实现肿瘤的高效诊断和治疗. 文章综述了近年来TPP盐在肿瘤诊断和治疗领域中的研究进展,以及在未来所面对的挑战.     

野西瓜挥发油诱导SGC-7901凋亡的初步研究

研究野西瓜挥发油诱导SGC-7901细胞凋亡的机制.采用流式细胞术分析野西瓜挥发油对SGC-7901细胞早期凋亡的影响;采用激光扫描共聚焦技术观测野西瓜挥发油对肿瘤细胞内Ca2+浓度变化的影响;采用流式细胞术分析野西瓜挥发油对SGC-7901细胞线粒体跨膜电位的影响.野西瓜挥发油可以诱导SGC-7901细胞发生早期凋亡,使肿瘤细胞内的Ca2+浓度升高,并降低细胞线粒体跨膜电位.野西瓜挥发油具有明显的抗肿瘤作用,其抗肿瘤机制为诱导肿瘤细胞凋亡.通过升高肿瘤细胞内的[Ca2+]i而激活了Ca2+依赖性的核酸内切酶,同时通过PT孔的开放,引起线粒体跨膜电位下降而导致细胞凋亡.     

表观遗传学药物诱导细胞凋亡机制系统生物学研究进展

表观遗传学药物就是通过改变表观遗传学修饰状态诱导肿瘤细胞发生凋亡的一类物质.表观遗传学药物能够在"线粒体呼吸链"等内源性凋亡相关通路内诱导特定基因发生时间特异性差异表达,并且表观遗传学修饰模式变化与基因表达和功能都密切相关.现阶段关于表观遗传学药物凋亡诱导机制的了解大部分是定性或描述性的,对于凋亡响应所涉及多个生物学过程的动态整合和内在调控机制的认识仍然十分缺乏.我们根据现阶段研究所存在的问题,提出合理化建议:首先,收集整理相关数据构建表观遗传学药物数据库.其次,基于跨组学数据分析的系统生物学建模策略,构建表观遗传学药物凋亡诱导模型.最后,评估不同表观遗传学修饰状态下细胞发生凋亡的时间和概率分布,从而促进表观遗传学药物诱导细胞凋亡机制的研究.     

重组绿豆BBI(6-33)结构域的抗肿瘤作用分析

通过大肠杆菌外源表达绿豆BBI蛋白抗肿瘤活性结构域,研究纯化后的BBI蛋白抗肿瘤活性结构域蛋白对肿瘤细胞增殖、凋亡和迁移的影响及引起肿瘤细胞凋亡的分子机制.MTT、DAPI染色、克隆形成、划痕实验等结果表明,重组BBI(6-33)域对A549等肿瘤细胞的增殖和迁移有抑制作用,对其凋亡则起促进作用.Western blot分析显示,重组BBI(6-33)域可激活caspase-3、caspase-9、p21等表达,提示其诱导肿瘤细胞凋亡作用可能主要是通过线粒体途径发挥的.     

啤酒花中异葎草酮体外抗肿瘤作用及机制研究

研究啤酒花(Humulus Lupulus L.)中成分异葎草酮(tetrahydro-iso-α-acid)对人胃腺癌细胞SGC-7901和人肝癌细胞HepG-2的体外抑制作用,并初步揭示其抗肿瘤的作用机制.以MTT法进行细胞毒测定;采用流式细胞仪观察异葎草酮对肿瘤细胞凋亡的影响;细胞线粒体跨膜电位(MMP)测定用罗丹明123(Rhodamine l23,Rh123)标记,以流式细胞仪检测.异葎草酮对SGC-7901和HepG-2的IC50分别为13.4μg/mL和11.58μg/mL.异葎草酮作用于SGC-7901和HepG-2细胞48 h后,肿瘤细胞均有明显凋亡峰出现.异葎草酮可以导致SGC-7901和HepG-2细胞内线粒体膜电位明显下降,并呈剂量依赖关系.结果表明,异葎草酮对肿瘤细胞SGC-7901及HepG-2均有较强抑制作用,这一作用是通过诱导肿瘤细胞凋亡实现的.异葎草酮是通过线粒体路径启动细胞凋亡的,而且诱导线粒体功能异常可能是其引起细胞凋亡发生的主要作用机理.     

线粒体间隙蛋白质转运方式的研究进展

所有的线粒体间隙蛋白质都是在胞质中合成的.这些蛋白质合成以后,通过三种方式被转运至线粒体间隙.第一种需要ATP水解供能,利用膜上的电化学势能进行转运;第二种需要利用蛋白质折叠时获得的能量完成转运;第三种需要利用线粒体间隙内的高亲合力的结合位点协助转运.本文将对这三种转运方式做一综述.     

茶多酚诱导肿瘤细胞凋亡的作用

对茶多酚诱导肿瘤细胞凋亡的作用及其可能的机理的研究进行了综述 ,提示茶多酚能被用来作为治疗肿瘤的辅助药物     

维生素E琥珀酸酯诱导肿瘤细胞凋亡作用机制的研究进展

维生素E琥珀酸酯是维生素E的衍生物。维生素E琥珀酸酯对肿瘤细胞有显著的凋亡杀伤作用,而对正常细胞没有明显的毒性反应。维生素E琥珀酸酯诱导肿瘤细胞凋亡的机制主要有线粒体途径、脂肪酸合成酶信号系统、MAPK途径、蛋白激酶C等途径。这些机制的研究发现可以为开发出新型与VES抗肿瘤作用同一靶分子的抗肿瘤药物开辟新途径。     

线粒体蛋白组研究进展

线粒体蛋白组是指在线粒体中出现的所有蛋白质的集合,包括线粒体自身基因组编码的和 由核基因组编码的蛋白质.线粒体作为真核生物的重要细胞器,它参与去除氧化、产生能量和还原 性物质等等一些重要的生命活动过程.这些功能都依赖于线粒体蛋白组中的蛋白河的相互作用.要 对其有一个较为全面的认识,就必须对其蛋白组进行广泛且深入的研究.根据现有的一些研究成 果,对线粒体蛋白组在起源与进化、跨膜运输、研究方法和计算机预测作了简要综述.     

Isolation and characterization of the gene for a yeast mitochondrial import receptor

We have previously identified an integral membrane protein (p32) from Saccharomyces cerevisiae as a receptor for protein import into mitochondria, and have localized it to the mitochondrial outer membrane at contact sites. Here we report isolation of the corresponding mitochondrial import receptor gene, termed MIR1. The deduced amino-acid sequence of p32 shows roughly 40% identity with proteins of bovine heart and rat liver that have been suggested to be mitochondrial phosphate carriers. Haploid cells carrying a disrupted MIR1 allele were unable to grow on a non-fermentable carbon source but grew in media containing glucose, indicating that the MIR1 protein is essential for mitochondrial function. Compared with wild type, amounts of some mitochondrial proteins were markedly reduced in cells containing a disrupted MIR1 allele, whereas levels of others were unchanged. This indicates that yeast contains more than one pathway for protein import into mitochondria.     

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.     

A cytosolic protein contains a cryptic mitochondrial targeting signal

Cytosolic dihydrofolate reductase from mouse contains a cryptic mitochondrial targeting sequence. If this sequence is attached to the amino terminus of 'passenger' proteins which by themselves cannot enter mitochondria, the resulting fusion proteins are transported into yeast mitochondria.     

A 42K outer-membrane protein is a component of the yeast mitochondrial protein import site

An engineered precursor protein that sticks in the import site of isolated yeast mitochondria can be specifically photo-crosslinked to a mitochondrial outer-membrane protein of relative molecular mass 42,000 (42K). This protein (termed import-site protein 42 or ISP 42) is exposed on the mitochondrial surface; antibodies against it block protein import into mitochondria. ISP 42 is the first identified component of the putative transmembrane machinery that imports proteins into mitochondria.     

Evolutionary conservation of biogenesis of beta-barrel membrane proteins

The outer membranes of mitochondria and chloroplasts are distinguished by the presence of beta-barrel membrane proteins. The outer membrane of Gram-negative bacteria also harbours beta-barrel proteins. In mitochondria these proteins fulfil a variety of functions such as transport of small molecules (porin/VDAC), translocation of proteins (Tom40) and regulation of mitochondrial morphology (Mdm10). These proteins are encoded by the nucleus, synthesized in the cytosol, targeted to mitochondria as chaperone-bound species, recognized by the translocase of the outer membrane, and then inserted into the outer membrane where they assemble into functional oligomers. Whereas some knowledge has been accumulated on the pathways of insertion of proteins that span cellular membranes with alpha-helical segments, very little is known about how beta-barrel proteins are integrated into lipid bilayers and assembled into oligomeric structures. Here we describe a protein complex that is essential for the topogenesis of mitochondrial outer membrane beta-barrel proteins (TOB). We present evidence that important elements of the topogenesis of beta-barrel membrane proteins have been conserved during the evolution of mitochondria from endosymbiotic bacterial ancestors.     

In vitro suppression of UGA codons in a mitochondrial mRNA

Although both prokaryotic and eukaryotic messenger RNAs can be easily translated in heterologous protein-synthesizing systems, attempts to achieve correct synthesis of mitochondrial proteins by translation of mitochondrial mRNAs in such systems have failed. In general, the products of synthesis are of low molecular weight and presumably represent fragments of mitochondrial proteins. These fragments display a strong tendency to aggregate. Explanations have included the use by mitochondria of codons requiring a specialized tRNA population and the fortuitous occurrence within genes of purine-rich sequences resembling bacterial ribosome binding sites. In addition, the long 5'-leader sequences present in many mitochondrial (mt) RNAs may also contribute to difficulties in mRNA recognition by heterologous ribosomes. Recent sequence analysis of human mtDNA suggests that the genetic code used by mammalian mitochondria deviates in a number of respects from the 'universal' code, the most striking of these being the use of the UGA termination codon to specify tryptophan. That this may also apply in yeast mitochondria has been shown by Fox and Macino et al., thus providing an obvious and easily testable explanation for the inability of heterologous systems to synthesize full-length mitochondrial proteins. We confirm this explanation and describe here the in vitro synthesis of a full-length subunit II of yeast cytochrome c oxidase in a wheat-germ extract supplemented with a partially purified mitochondrial mRNA for this protein and a UGA-suppressor tRNA from Schizosaccharomyces pombe.     

Rapid regulation of steroidogenesis by mitochondrial protein import

Most mitochondrial proteins are synthesized on cytoplasmic ribosomes and imported into mitochondria. The imported proteins are directed to one of four submitochondrial compartments--the outer mitochondrial membrane, the inner mitochondrial membrane, the intramembraneous space, or the matrix--where the protein then functions. Here we show that the steroidogenic acute regulatory protein (StAR), a mitochondrial protein required for stress responses, reproduction, and sexual differentiation of male fetuses, exerts its activity transiently at the outer mitochondrial membrane rather than at its final resting place in the matrix. We also show that its residence time at this outer membrane and its activity are regulated by its speed of mitochondrial import. This may be the first example of a mitochondrial protein exerting its biological activity in a compartment other than that to which it is finally targeted. This system enables steroidogenic cells to initiate and terminate massive levels of steroidogenesis within a few minutes, permitting the rapid regulation of serum steroid hormone concentrations.     

Requirement for hsp70 in the mitochondrial matrix for translocation and folding of precursor proteins

By analysis of a temperature-sensitive yeast mutant, a heat-shock protein in the matrix of mitochondria, mitochondrial hsp70 (Ssc1p), is found to be involved both in translocation of nuclear-encoded precursor proteins across the mitochondrial membranes and in (re)folding of imported proteins in the matrix.     

线粒体蛋白转运系统的序列相似性分析

通过在27个不同进化层次物种的基因组和蛋白组中搜索酵母线粒体蛋白转运系统亚基的同源序列, 并进一步分析了同源亚基序列相似性与其所在线粒体位置的关系. 结果表明, 位于线粒体相同位置的模块有类似的序列相似性曲线, 相似性曲线在模块内部一般有波峰和波谷. 从线粒体外膜到基质, 序列相似性整体升高. 线粒体蛋白转运系统亚基与一些功能不相关的蛋白也表现出序列相似关系, 且这些亚基多集中在线粒体的内膜和外膜.