Smac及其类似物与肿瘤相关性研究进展

Smac是一种存在线粒体中并具有促凋亡作用的蛋白,2000年被两个不同实验室同时发现报道,Smac主要通过参与细胞凋亡的线粒体途径和死亡受体途径的下游反应,特异性地与IAPs结合,解除IAPs对caspase的抑制效应从而促进细胞凋亡。在肿瘤细胞中,Smac的过表达可以抑制或延缓肿瘤的发生发展过程,提高细胞浆Smac含量可增强细胞对放化疗的敏感性；人工合成的Smac类似物可通过级联放大效应提高肿瘤细胞对放化疗的敏感性,具有高效、低毒、高通透性等优点,为肿瘤的治疗提供了新的方法和思路,具有重要的临床意义。本文就Smac、Smac类似物与肿瘤的相关性研究进展做一综述。     

Smac对胰腺癌细胞凋亡的作用及研究进展

胰腺癌是消化系统恶性程度最高、预后最差的肿瘤之一,目前的治疗手段并未取得令人满意的疗效。Smac是一种新型的线粒体源性促凋亡蛋白,参与细胞凋亡的线粒体通路和死亡受体通路反应,主要通过拮抗X-相关凋亡抑制蛋白(XIAP)对caspase的抑制作用促进细胞凋亡。研究表明Smac与肿瘤的发生发展、放化疗疗效具有相关性,但关于Smac在胰腺癌中的作用的研究甚少,本文就Smac在胰腺癌中表达、发生发展及治疗等方面研究进展作一论述。     

Smac与肿瘤

Smac Smacl Second mitochondrical activator of caspase是一种新发现的线粒体蛋白,在细胞凋亡过程中起着重要作用;当细胞发生凋亡时,其与细胞色素C一起被释放进入细胞浆,在细胞色素C/Apaf-1/Caspase-9凋亡途径中促进Casepase（含半胱氨酸的天冬氨酸特异性蛋白酶）的激活。Smac通过解除凋亡抑制蛋白对Caspase-3、Caspase-7、Casepase-9的抑制作用而诱导细胞凋亡。Smac的高表达可以增加细胞对凋亡刺激信号的敏感性,这对于肿瘤的发生、发展,以及肿瘤的治疗具有重要意义。     

Livin和Smac的相关性研究进展

Livin蛋白是凋亡抑制蛋白家族IAPs的新成员,其主要功能是通过BIR区与胱天蛋白酶Caspase-3,7,9结合并抑制其活性,从而抑制细胞凋亡。Smac是从线粒体膜间区释放入细胞质的重要凋亡调节因子,     

Smac与肿瘤

Smac Smacl Second mitochondrical activator of caspase是一种新发现的线粒体蛋白,在细胞凋亡过程中起着重要作用;当细胞发生凋亡时,其与细胞色素C-起被释放进入细胞浆,在细胞色素C/Apaf-1/Caspase-9凋亡途径中促进Casepase(含半胱氨酸的天冬氨酸特异性蛋白酶)的激活.Smac通过解除凋亡抑制蛋白对Caspase-3、Caspase-7、Casepase-9的抑制作用而诱导细胞凋亡.Smac的高表达可以增加细胞对凋亡刺激信号的敏感性,这对于肿瘤的发生、发展,以及肿瘤的治疗具有重要意义.     

肺癌外周血中Survivin mRNA表达及其对预后的判断价值

<正>Survivin是新近发现的凋亡抑制蛋白(IAP)家族中新的一员,其抗凋亡作用的机制可通过Caspase途径和非Caspase途径实现,属于一种结构独特的哺乳类凋亡抑制蛋白(IAPs)家族成员,Survivin同时具有肿瘤组织特异性高表达的特性,研究已证实多种常见肿瘤如胃癌、大肠癌、     

Livin——癌症治疗的新靶点

Livin是IAPs(inhibitorsofapoptosisproteins,IAPs)蛋白家族的新成员 ,有BIR和RING指结构域 ,能够与Caspas es蛋白结合 ,抑制其介导的细胞凋亡。它在大多数正常成人组织中不表达、在一些肿瘤细胞中的高表达 ,与肿瘤的关系为人们所关注 ,是肿瘤治疗的潜在靶点。     

大鼠脑缺血/再灌注损伤时X连锁凋亡抑制蛋白和Smac表达及神经调节素的干预作用

目的观察神经调节素-1β(NRG-1β)对缺血/再灌注后脑组织X连锁凋亡抑制蛋白(XIAP)和次级线粒体源性caspase激活剂(Smac)表达的影响,探讨NRG-1β对脑缺血/再灌注损伤的保护作用。方法成年健康♂Wister大鼠110只,随机分为3组:假手术组(n=10),对照组(n=50)和治疗组(n=50)。治疗组动物单剂量给予NRG-1β干预治疗。应用原位末端标记技术(TUNEL)检测细胞凋亡,免疫荧光双标法和免疫印迹法检测脑组织XIAP和Smac蛋白的表达。结果缺血/再灌注能诱导脑组织细胞凋亡,随着缺血时间的延长,凋亡细胞数明显增加,NRG-1β处理能明显减少脑组织皮质区和纹状体区凋亡细胞数(P<0.05)。缺血/再灌注可诱导XIAP和Smac蛋白的表达,NRG-1β处理能上调XIAP和下调Smac的表达,协调神经细胞中XIAP/Smac的比例(P<0.05)。结论脑缺血后给予NRG-1β处理,可能通过协调XIAP/Smac蛋白的表达水平,调节细胞凋亡的发展过程,避免神经元发生不可逆损伤,从而对缺血/再灌注损伤有积极的保护作用。     

ING4基因与肿瘤研究新进展

ING4基因是肿瘤抑制因子家族的新成员,近来研究发现,ING基因在正常组织中表达丰富,但在多种恶性肿瘤组织,如乳腺癌、胶质瘤、肺癌等中表达明显下调,ING4可通过增强p53基因的活性、恢复细胞间接触抑制、抑制肿瘤血管生成、抑制HIF的活性而抑制肿瘤的生长,还能诱导细胞凋亡,增加肿瘤细胞对放化疗的敏感性,本研究对ING4基因与肿瘤研究的新进展进行综述。     

以IAPs为靶点的抗肿瘤研究进展

凋亡抑制因子(inhibitor of apoptosis proteins,IAPs)是一类高度保守的内源性抗细胞凋亡因子家族,主要通过抑制caspase活性和参与调节核因子NF-κB的作用抑制细胞凋亡。caspases蛋白酶的级联激活是凋亡过程的中心环节,Bcl-2家族蛋白和IAPs家族蛋白是主要控制因素。近年来发现,某些IAPs成员异常表达与肿瘤密切相关,成为肿瘤治疗的潜在靶点。因此,该文主要综述了与IAPs家族相关的蛋白以及以IAPs为靶点的抗肿瘤研究。     

转染Smac对肝癌细胞凋亡的影响

目的探讨过表达Smac基因对人肝癌HepG2细胞凋亡、细胞周期及凋亡相关蛋白Survivin、半胖氨酸蛋白酶-3（Caspase-3）表达的影响。方法从人K562细胞中扩增Smac cDNA,构建含Smac cDNA的真核表达载体pEGFP-C1-Smac,并转染人肝癌细胞HepG2。流式细胞仪检测分析细胞凋亡百分率,凋亡相关蛋白Survivin、Caspase-3的表达及细胞周期。结果转染Smac基因组、转染空载体组、未转染组细胞凋亡率差异有统计学意义（P〈0.05）。转染Smac基因组细胞凋亡率高于未转染组,也高于转染空载体组细胞,差异均有统计学意义（P〈0.05）。转染Smac基因组细胞Survivin的表达显著高于未转染组,也显著高于转染空载体组细胞,差异均有统计学意义（P〈0.05）。未转染组、转染空载体组、转染Smac基因组中Caspase-3蛋白表达差异无统计学意义（P〉0.05）。未转染组、转染空载体组、转染Smac基因组HepG2细胞的G0/G1期、S期、G2/M各期细胞比例差异无统计学意义（P〉0.05）。结论过表达Smac可诱导人肝癌HepG2细胞凋亡率增加,促进细胞凋亡。     

Transfection of Smac/DIABLO sensitizes drug-resistant tumor cells to TRAIL or paclitaxel-induced apoptosis in vitro

Smac/DIABLO is a recently identified protein released from mitochondria in response to apoptotic stimuli and promotes apoptosis by antagonizing inhibitor of apoptosis proteins (IAPs). In this study, we observed depressed Smac/DIABLO and increased XIAP expression in ovarian epithelial tissues ordered by normal, benign and malignant epithelia. In epithelial ovarian cancer (EOC), the expression of Smac/DIABLO decreased with the malignancy. Smac/DIABLO expression showed no correlation with TRAIL sensitivity, while lower Smac/DIABLO expression and decreased release of Smac/DIABLO from mitochondria upon apoptosis stimuli were observed in paclitaxel-resistant A2780/pac cells as compared to the sensitive controls. Ectopic Smac/DIABLO alone inhibited cell growth, arrested cells in G0/G1 phase, and sensitized drug-resistant EOC cells to TRAIL or paclitaxel-induced apoptosis. Increased apoptosis was associated with the down-regulation of XIAP, FLIP, and up-regulation of Smac/DIABLO, cytochrome c, p53, along with increased activity of caspase-3. Thus, over-expression of Smac/DIABLO is a promising strategy for drug-resistant ovarian cancer treatment.     

Smac/DIABLO and colon cancer

Apoptosis is a genetically programmed process of controlled and orderly cell suicide, which is critical for multicellular organisms during development and tissue homeostasis. In cancer, the ratio of apoptosis to cell division is altered, resulting in a net gain of malignant tissue. Tumor cells may acquire resistance to apoptosis by the expression of anti-apoptotic proteins, or by the down-regulation or mutation of pro-apoptotic mediators. In the classic pathway of apoptosis, this process is primarily coordinated by activation of caspases. Decreased expression of caspases inversely correlates with the aggressiveness of cancer. Increased activity of caspases renders cancer cells susceptible to chemoradiotherapeutic modalities. Thus, caspase activity is pivotal in carcinogenesis. The functions of activated caspases are inhibited by the binding of inhibitors of apoptosis (IAPs). The function of IAPs is regulated by pro-apoptotic protein Second Mitochondria-Derived Activator of Caspases (Smac) or Direct IAP Binding Protein with low isoelectric point, pI (DIABLO). Induction of apoptosis leads to increased mitochondrial permeability to Smac/DIABLO, which adheres to IAPs inhibiting their caspase-binding activity. The role of Smac/DIABLO, therefore, may have significant diagnostic and therapeutic features in carcinogenesis. The role of Smac/DIABLO in colorectal carcinogenesis is ill defined. Data continues to accumulate to suggest that decreased levels of Smac/DIABLO may be important in chemoradiation-resistance to apoptosis in advanced colon cancer. The aim of this review is to provide the available evidence of the role of Smac/DIABLO in colon carcinogenesis.     

Predominant enhancement of apoptosis induced by methyl jasmonate in bladder cancer cells: therapeutic effect of the Antp-conjugated Smac peptide

Methyl jasmonate (MJ) has recently attracted attention as a promising antitumoral compound because of its highly specific proapoptotic properties in a wide range of malignancies. However, the high doses required to achieve a therapeutic benefit have limited its clinical development. Here, we hypothesize that the family of inhibitor of apoptosis proteins (IAPs) may inhibit MJ-mediated apoptosis in cancer cells. We combined MJ with the IAPs inhibitor, the second mitochondria-derived activator of caspases (Smac) peptide to treat bladder cancer cells. The results showed that the combination of MJ and Smac peptide enhanced the apoptosis-inducing effect in a synergistic manner by releasing and activating IAPs-bounding caspase-3. These findings suggest that the inhibition of IAPs could overcome the resistance of cancer cells to MJ.     

凋亡调控蛋白Smac和Activated caspase-3在卵巢粘液腺癌中的表达及意义

目的了解凋亡调控蛋白Smac和Activated caspase-3在卵巢粘液性肿瘤中的表达及临床意义。方法采用免疫组织化学(S-P法)检测90例卵巢粘液性囊腺癌和36例正常卵巢组织中Smac和Activated caspase-3蛋白的表达水平。结果 Smac、Activated caspase-3在粘液性囊腺癌中的表达率分别为77.78%、54.4%;而在正常卵巢中的表达率分别为52.78%、86.1%。结论凋亡调控蛋白Smac和Activated caspase-3表达的紊乱和卵巢粘液性囊腺癌的发生有关,两者可能成为判断预后的指标。     

Livin和Smac在膀胱移行细胞癌中的表达及相关性研究

目的:探讨Livin蛋白和Smac蛋白在膀胱移行细胞癌(BTCC)中的表达及两者的相关性.方法:应用免疫组化SABC法检测42例BTCC组织和18例癌旁正常黏膜组织中Livin蛋白和Smac蛋白的表达情况,并分析两者与BTCC临床病理特征的关系.结果:Livin蛋白和Smac蛋白在BTCC组织中的阳性表达率分别73.8％(31/42)和28.6％(12/42),而在18例癌旁正常黏膜组织中分别为0和77.8％(14/18),两者在癌和癌旁间的表达差异均有统计学意义(P＜0.01);在有无复发的患者中Livin蛋白和Smac蛋白的表达差异均有统计学意义(P＜0.05),不同性别、年龄、组织学分级、临床分期、肿瘤数目Livin蛋白和Smac蛋白在BTCC中的表达差异均无统计学意义.Livin蛋白和Smac蛋白在BTCC组织中的表达呈负相关(r=-0.462,P＜0.05).结论:Livin蛋白高表达和Smac蛋白低表达或缺失表达可能是导致BTCC的发生及复发的原因,两者可能是BTCC细胞凋亡信号传导网络中的重要一环.     

Smac和survivin基因在骨肉瘤中的表达及其临床意义

目的探讨人骨肉瘤组织中Smac和survivin基因表达状态,及其对骨肉瘤生物学行为的影响。方法采用免疫组织化学技术(SABC法)检测46例骨肉瘤、10例骨软骨瘤组织中Smac和survivin蛋白表达,比较二者表达与骨肉瘤主要临床病理参数的关系。结果Smac和survivin基因在骨软骨瘤组织表达分别为3例、2例,骨肉瘤中分别为29例(63%)和31例(67%);Smac表达率与骨肉瘤组织学分级、WHO分型无关,与转移有关(P<0.05),Survivin表达率与骨肉瘤组织学分级无关,与WHO分型及转移有关(P<0.05);骨肉瘤中Smac和survivin基因表达呈正相关(r=0.506,P<0.01)。结论Smac和survivin基因高表达于骨肉瘤组织中,与骨肉瘤生物学行为密切相关,二者可能共同参与骨肉瘤的发生发展。     

Role of genomics-based strategies in overcoming chemotherapeutic resistance

As cancer is being recognized as a failure of apoptosis, apoptosis-based strategies are being designed. Caspases are critical for the induction of apoptosis and their decreased expression is correlated with increased grade of cancer, while increased expression of caspases rendered the cancer cells susceptible to chemotherapy. However, the endogenous functions of caspases are inhibited by inhibitors of apoptosis (IAPs) that bind activated caspases. Methods to suppress the function of IAP induced apoptosis in chemo-resistant cancer cells. The function of IAPs is inhibited by Second Mitochondria-Derived Activator Of Caspase (Smac) or Direct IAP Binding Protein With Low Pi (DIABLO). Upon apoptotic stimulus Smac/DIABLO is released from the mitochondria, which binds to IAPs and inhibits their caspase-binding activity. Overexpression of Smac/DIABLO sensitized neuroblastoma to TRAIL (TNFalpha-Related Apoptosis-Inducing Ligand). Activation of TRAIL pathway has become an important method of inducing apoptosis except in TRAIL-resistant cells. However, treatment of these cells with other cytotoxic drugs sensitizes them to TRAIL, providing effective therapeutic advantages. In addition to activating apoptotic pathways, inhibiting or suppression of cell proliferation is necessary to sensitize cancer cells to apoptosis. Critical among these proteins are NFkappaB and Akt. NFkappaB blocked apoptosis by interfering with the function of TNFalpha/TRAIL and/or through the activation of antiapoptotic proteins of the Bcl2 family. Similarly, Akt mediate cell survival via the regulation of cell survival proteins and by blocking the function of proapoptotic Bad by phosphorylation. Altering the expression of Akt by dominant negative constructs or by expression of PTEN interferes with Akt function. In summary, this review points out the complexity of interactions of the cell survival and death pathways and highlights some methods to manipulate them to achieve therapeutic advantage.     

Potent bivalent Smac mimetics: effect of the linker on binding to inhibitor of apoptosis proteins (IAPs) and anticancer activity

We have synthesized and evaluated a series of nonpeptidic, bivalent Smac mimetics as antagonists of the inhibitor of apoptosis proteins and new anticancer agents. All these bivalent Smac mimetics bind to full-length XIAP with low nanomolar affinities and function as ultrapotent antagonists of XIAP. While these Smac mimetics bind to cIAP1/2 with similar low nanomolar affinities, their potencies to induce degradation of cIAP1/2 proteins in cells differ by more than 100-fold. The most potent bivalent Smac mimetics inhibit cell growth with IC(50) from 1 to 3 nM in the MDA-MB-231 breast cancer cell line and are 100 times more potent than the least potent compounds. Determination of intracellular concentrations for several representative compounds showed that the linkers in these bivalent Smac mimetics significantly affect their intracellular concentrations and hence the overall cellular activity. Compound 27 completely inhibits tumor growth in the MDA-MB-231 xenografts while causing no signs of toxicity in the animals.