Survivin小分子抑制剂的研究进展

Survivin是凋亡抑制蛋白家族的一员,在抑制细胞凋亡、调控细胞周期、参与血管形成等方面发挥重要的生物学功能。Survivin在多种肿瘤组织中过量表达,与肿瘤不良预后和耐药性密切相关。Survivin作为一种潜在的肿瘤治疗靶点,其小分子抑制剂用于肿瘤治疗的研究为人们所关注。概述了Survivin的结构、功能及其在肿瘤组织中的特异性表达,综述了目前靶向Survivin的小分子抑制剂的研究进展。     

抗增殖蛋白在肿瘤发生发展过程中扮演多种角色

抗增殖蛋白（prohibitins,PHBs）是一类进化保守的重要蛋白质。哺乳动物细胞中,抗增殖蛋白家族含有2个同源亚型PHB1和PHB2。PHBs涉及多种细胞功能,包括细胞增殖、细胞迁移和细胞凋亡。PHBs的亚细胞定位不同决定其行使不同的功能。细胞膜上的PHBs能够调节膜运输,并与细胞增殖迁移相关。细胞核内的PHBs参与调控转录和细胞周期。线粒体内膜上的PHBs参与维持线粒体基因组和线粒体形态的稳定,并参与线粒体内的凋亡途径。另外,PHBs可以在细胞核和线粒体之间“穿梭”,是细胞核与线粒体交流的重要媒介。近年来,PHBs的研究不断深入,发现PHBs与多种肿瘤的发生和发展密切相关。本文以PHBs在肿瘤发生发展过程中扮演的角色为切入点,从蛋白质的结构和定位,在肿瘤的发生、发展、迁移和凋亡中的作用及其靶向药物几方面进行综述。进一步揭示PHBs在不同类型肿瘤发生发展进程中的分子机制,为开发新的高效的药物靶点奠定了理论基础。     

肿瘤坏死因子家族及其相关药物的研究进展

细胞凋亡是进化保守的重要生物学过程,具有重要的生理和病理作用,如在免疫系统的发育与稳态以及多种疾病（包括肿瘤）的发 生、发展、预后及治疗等过程中起重要作用。因此,近年来参与细胞凋亡信号转导的肿瘤坏死因子（TNF）/TNF 受体（TNFR）家族的重要 成员TNFα/TNFR、Fas/FasL和TRAIL/TRAILR成为重要的药物靶点,并开发出多个相关靶向药物,尤其是生物药物,其中有些在临床疗 效和商业上获得巨大成功。简介参与细胞凋亡信号转导的TNF/TNFR家族重要成员,着重对其通过介导细胞凋亡而发挥的生物学作用及其 相关药物研发作一综述,希望对我国的药物研发有所裨益。     

USP10的分子功能及在肿瘤中的研究进展

泛素特异性蛋白酶10(ubiquitin-specific protease 10,USP10)是去泛素化酶(deubiquitinating enzymes,DUBs)家族中的一个重要成员。近年来的研究发现USP10参与了细胞中多种生命活动的调节,如细胞增殖、细胞凋亡、DNA损伤修复、炎症应答等。同时,USP10在多种肿瘤的发生发展过程中表现出其重要作用。现就USP10的分子功能及其在肿瘤中的研究进展进行综述,以期发现与USP10相关的某些关键的分子机制,为肿瘤诊断与治疗提供参考。     

FGF-2 在细胞凋亡中的作用机制

成纤维细胞生长因子2(fibroblast growth factor 2,FGF-2)具有多种细胞生物学功能。FGF-2在肿瘤组织中呈高水平表达状态,且可抑制多种化疗药物的促凋亡作用,从而曾为肿瘤细胞存活的重要刺激因素。但也有研究表明FGF-2可诱导部分细胞的分化和凋亡。鉴于FGF-2在肿瘤的发生发展中发挥的重要作用,FGF-2与细胞凋亡的关系及其相应的调节机制成为有待于深入研究和迫切需要解决的问题。本文主要阐述在细胞凋亡通路中,FGF-2关键分子的作用机制及其最新研究进展。     

电压门控性钾离子通道与肿瘤关系的研究

电压门控性钾离子通道是钾离子通道的一个亚型,广泛地分布于细胞膜上,在调节细胞静息膜电位和膜电位复极化中发挥着重要的作用.近年来的研究表明电压门控性钾离子通道也表达于多种肿瘤细胞中,并通过影响细胞膜电压、改变细胞体积等方式影响着肿瘤细胞的增殖和周期,这也为肿瘤的治疗提供了新的靶点.     

死亡受体信号通路耐受机制及肿瘤治疗CSCD

死亡受体介导的凋亡通路是治疗肿瘤的理想方案。凋亡通路中具有复杂的调控机制,控制细胞的生死存亡。其中有多类抗凋亡因子,致使肿瘤细胞对凋亡信号耐受,使得凋亡在肿瘤治疗领域的应用受限。临床前体外细胞及裸鼠研究发现,单独靶向这些死亡受体或抗凋亡因子的药物或与传统化疗联合可以有效引起肿瘤细胞凋亡,但临床II期实验没有明显治疗效果。本综述总结分析多种抗凋亡因子产生的耐受机制以及靶向药物的研究现状,提出同时靶向死亡受体、c-FLIP及IAP是治疗肿瘤的理想方案。     

钙信号在光动力疗法中的产生及作用

光动力疗法是基于光敏剂选择性地积聚在肿瘤组织中,肿瘤接受光照后凋亡或坏死的一种细胞毒性治疗方法.光敏剂的亚细胞定位决定了细胞光敏损伤的初始位置,线粒体、内质网、细胞膜、溶酶体,细胞骨架等均可成为光敏损伤的靶点.细胞内Ca2 作为一个广泛意义上的信号分子,参与了多种信号转导途径,在光动力疗法诱导肿瘤细胞凋亡过程中起了重要作用.从光动力疗法造成的亚细胞损伤出发,探讨了光动力疗法中钙信号的产生机制,并简要介绍了钙信号在光动力疗法诱导肿瘤细胞凋亡中的作用机制.     

IAP家族分子与肿瘤靶向治疗

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的作用而抑制细胞凋亡。细胞抗凋亡机制在肿瘤发生、发展以及肿瘤耐药性形成中发挥重要作用。肿瘤细胞高表达IAPs是导致肿瘤细胞抵抗凋亡的关键。细胞凋亡调控异常与肿瘤细胞耐药密切相关,增强肿瘤细胞对化疗药物的敏感性成为近年来肿瘤治疗的重要策略之一。该文综述了IAP家族蛋白的结构、生物学特性及其作为肿瘤治疗靶点的研究进展。     

白细胞介素-8与肿瘤免疫逃逸

IL-8是趋化因子CXC家族的一员,是一种多细胞来源的细胞因子,在细胞的多种炎症反应中起调节作用,并且在自身免疫性疾病中也发挥重要作用。IL-8通过与细胞膜上的CXC趋化因子受体CXCR1和CXCR2相互作用,激活偶联的G蛋白,由G蛋白进一步激活PLC、AC、PLD、PI3K、JAK2及Ras等信号分子,从而调控基因表达、细胞增殖和分化、细胞代谢、细胞运动及血管生成等多种细胞生命过程。IL-8在多种恶性肿瘤细胞中表达量升高,其高表达与肿瘤细胞增殖、迁移、侵袭、血管生成及上皮间充质转化有密切联系。肿瘤免疫逃逸是肿瘤细胞产生和转移过程中的主要特征之一,肿瘤细胞可以通过多种机制使得人体免疫系统无法对其进行正常的识别和攻击,从而导致肿瘤细胞在体内存活,并且不断增殖和转移,而肿瘤细胞、免疫细胞以及肿瘤微环境中其他相关组分均可以促进肿瘤免疫逃逸。IL-8作为一种炎性趋化因子,已被证明在肿瘤免疫逃逸中具有重要作用,其可通过诱导肿瘤细胞PD-L1表达、抑制肿瘤细胞凋亡、促进肿瘤细胞EMT进程、促进肿瘤微环境血管生成、招募免疫抑制性细胞等五个方面介导肿瘤免疫逃逸。IL-8中和抗体和CXCR1/2拮抗剂在抗肿瘤治疗方面已经显示出较好的治疗效果。     

Stemming the tide: glycosphingolipid synthesis inhibitors as therapy for storage diseases

Glycosphingolipids (GSLs) are plasma membrane components of every eukaryotic cell. They are composed of a hydrophobic ceramide moiety linked to a glycan chain of variable length and structure. Once thought to be relatively inert, GSLs have now been implicated in a variety of biological processes. Recent studies of animals rendered genetically deficient in various classes of GSLs have demonstrated that these molecules are important for embryonic differentiation and development as well as central nervous system function. A family of extremely severe diseases is caused by inherited defects in the lysosomal degradation pathway of GSLs. In many of these disorders GSLs accumulate in cells, particularly neurons, causing neurodegeneration and a shortened life span. No effective treatment exists for most of these diseases and little is understood about the mechanisms of pathogenesis. This review will discuss the development of a new approach to the treatment of GSL storage disorders that targets the major synthesis pathway of GSLs to stem their cellular accumulation.     

MicroRNA 与肿瘤的相关研究进展

微小RNA(microRNAs,miRNA)是一类22个核苷酸左右的非编码调控RNA。可以通过切割mRNA或者是抑制翻译两种机制,在转录后水平发挥调控生物生长发育的重要作用。目前的研究已经发现microRNA参与调控发育、细胞分化、细胞凋亡等多种生理过程。目前已证实miRNA参与肿瘤发生和进展,miRNA表达谱是肿瘤诊断和预后的指标,miRNA突变、缺失或表达水平的异常与人类肿瘤密切相关,它发挥类似于癌基因或抑癌基因的作用,参与肿瘤细胞的增殖、分化和细胞凋亡过程。本文就miRNA在肿瘤发生发展以及诊断治疗方面的研究进展作一综述。     

Pathophysiological roles and applications of glycosphingolipids in the diagnosis and treatment of cancer diseases

Glycosphingolipids (GSLs) are major amphiphilic glycolipids present on the surface of living cell membranes. They have important biological functions, including maintaining plasma membrane stability, regulating signal transduction, and mediating cell recognition and adhesion. Specific GSLs and related enzymes are abnormally expressed in many cancer diseases and affect the malignant characteristics of tumors. The regulatory roles of GSLs in signaling pathways suggest that they are involved in tumor pathogenesis. GSLs have therefore been widely studied as diagnostic markers of cancer diseases and important targets of immunotherapy. This review describes the tumor-related biological functions of GSLs and systematically introduces recent progress in using diverse GSLs and related enzymes to diagnose and treat tumor diseases. Development of drugs and biomarkers for personalized cancer therapy based on GSL structure is also discussed. These advances, combined with recent progress in the preparation of GSLs derivatives through synthetic biology technologies, suggest a strong future for the use of customized GSL libraries in treating human diseases.     

Connective tissue growth factor (CTGF) and cancer progression

Connective tissue growth factor (CTGF) is a member of the CCN family of secreted, matrix-associated proteins encoded by immediate early genes that play various roles in angiogenesis and tumor growth. CCN family proteins share uniform modular structure which mediates various cellular functions such as regulation of cell division, chemotaxis, apoptosis, adhesion, motility, angiogenesis, neoplastic transformation, and ion transport. Recently, CTGF expression has been shown to be associated with tumor development and progression. There is growing body of evidence that CTGF may regulate cancer cell migration, invasion, angiogenesis, and anoikis. In this review, we will highlight the influence of CTGF expression on the biological behavior and progression of various cancer cells, as well as its regulation on various types of protein signals and their mechanisms.     

Redox signaling: Potential arbitrator of autophagy and apoptosis in therapeutic response

Redox signaling plays important roles in the regulation of cell death and survival in response to cancer therapy. Autophagy and apoptosis are discrete cellular processes mediated by distinct groups of regulatory and executioner molecules, and both are thought to be cellular responses to various stress conditions including oxidative stress, therefore controlling cell fate. Basic levels of reactive oxygen species (ROS) may function as signals to promote cell proliferation and survival, whereas increase of ROS can induce autophagy and apoptosis by damaging cellular components. Growing evidence in recent years argues for ROS that below detrimental levels acting as intracellular signal transducers that regulate autophagy and apoptosis. ROS-regulated autophagy and apoptosis can cross-talk with each other. However, how redox signaling determines different cell fates by regulating autophagy and apoptosis remains unclear. In this review, we will focus on understanding the delicate molecular mechanism by which autophagy and apoptosis are finely orchestrated by redox signaling and discuss how this understanding can be used to develop strategies for the treatment of cancer.     

Drosophila glucosylceramide synthase: a negative regulator of cell death mediated by proapoptotic factors

Glucosylceramide synthase (GlcT-1) catalyzes the formation of glucosylceramide (GlcCer), the core structure of major glycosphingolipids (GSLs), from ceramide and UDP-glucose. Ceramide and its metabolites, such as sphingosine-1-phosphate, are now known to be important mediators of apoptosis and cell survival. Recently, we have shown that GlcT-1 functions to regulate intracellular ceramide levels via glycosylation of ceramide. In this study, we employ the fruit fly Drosophila melanogaster as a model system for understanding the in vivo roles of GlcT-1. We isolated and characterized a GlcT-1 homologue (DGlcT-1) from Drosophila. When DGlcT-1 was expressed in GM-95 cells deficient in GSLs (because of the absence of GlcT-1 activity), these cells regained the ability to synthesize GSLs. Northern blot and in situ hybridization analyses revealed that the expression of DGlcT-1 mRNA was ubiquitous throughout development, suggesting that DGlcT-1 is important for development and differentiation. Indeed, RNA interference experiments demonstrated that the loss of GlcT-1 function enhances apoptotic cell death. Conversely, targeted expression of GlcT-1 partially rescued cell death caused by the proapoptotic factors Reaper and Grim, suggesting that ceramide generation might be one signal pathway that executes the cell death program. We also found that GlcT-1 localized not only in the Golgi apparatus but also in the perinuclear endoplasmic reticulum, providing the first visual evidence of GlcT-1 in membranes. These results indicate that GlcT-1 might down-regulate ceramide generated in these membranes.     

The molecular control of DNA damage-induced cell death

Because of the singular importance of DNA for genetic inheritance, all organisms have evolved mechanisms to recognize and respond to DNA damage. In metazoans, cells can respond to DNA damage either by undergoing cell cycle arrest, to facilitate DNA repair, or by undergoing cell suicide. Cell death can either occur by activation of the apoptotic machinery or simply be a consequence of irreparable damage that prevents further cell division. In germ cells, mechanisms for limiting alterations to the genome are required for faithful propagation of the species whereas in somatic cells, responses to DNA damage prevent the accumulation of mutations that might lead to aberrant cell proliferation or behavior. Several of the genes that regulate cellular responses to DNA damage function as tumor suppressors. The clinical use of DNA damaging agents in the treatment of cancer can activate these tumor suppressors and exploits the cellular suicide and growth arrest mechanisms that they regulate. It appears that in some but not all types of tumors the propensity to undergo apoptosis is a critical determinant of their sensitivity to anti-cancer therapy. This review describes current understanding of the molecular control of DNA damage-induced apoptosis with particular attention to its role in tumor suppression and cancer therapy.     

Programs for Cell Death: Apoptosis is Only One Way to Go

Cell death programs are major players in tissue homeostasis, development and cellular stress responses. A prominent cause of malignant transformation is the cumulative genetic alterations in pathways that regulate cellular growth and death. The processes that govern cell death following genotoxic stress are a major focus of basic research and are also very relevant to translational research in clinical oncology: understanding cell death following cancer therapy is essential for designing new treatment modalities. Cell death is usually, and sometimes automatically, linked with one of its major programs, apoptosis. Recent advances have led, however, to the emergence of additional, non-apoptotic cell death pathways, each with its triggers and readouts. Genotoxic stress appears to induce several cell death pathways, only part of which fall within the classical definition of apoptosis. Accordingly, solid tumor cells that are refractive to apoptosis were shown to die via non-apoptotic mechanisms. Recently we demonstrated that mitotic cell death induced by DNA damage in cells with defective G2/M checkpoint is mechanistically distinct from apoptosis. This review outlines recent advances in the understanding of molecular networks operative in apoptotic and non-apoptotic cell death mechanisms and their cross-talks.     

ASPP2: A Gene that Controls Life and Death in Vivo

The fundamental role of apoptosis in tumor prevention and the important role of p53 in this process are now universally recognized. Recently, several families of p53-binding proteins have been shown to influence p53’s decision to direct the cells either in the apoptotic pathway or in cell cycle arrest. Among them, the ASPP family specifically regulate p53-dependent apoptosis. Its member ASPP2 was discovered more than 10 years ago as a binding partner of p53 and its role as a positive regulator of p53 mediated apoptosis has been clearly established in vitro. However, its physiological importance in vivo has just emerged through the generation and characterisation of the ASPP2-deficient mice. We now know that ASPP2 is a haploinsufficient tumor suppressor and an important activator of p53 during mouse development and tumor suppression in vivo. ASPP2 might be a novel target for future cancer therapy.