肿瘤抑制基因p53与自噬

近年来研究表明,p53是一种抑癌基因,作为一种重要的转录因子,其在细胞周期阻滞、凋亡中都发挥着重要作用。自噬是在细胞营养物质匮乏条件下蛋白质动态降解的过程,自噬性细胞死亡是不同于细胞凋亡的另一种细胞程序性死亡模式,被称之为II型程序性死亡,细胞凋亡为I型程序性死亡。研究表明,肿瘤的发生发展与自噬性细胞死亡相关,作为肿瘤抑制基因p53也参与了自噬活性的调节。本文对此做一简要概述。     

肿瘤抑制基因p53与自噬

近年来研究表明,p53是一种抑癌基因,作为一种重要的转录因子,其在细胞周期阻滞、凋亡中都发挥着重要作用。自噬是在细胞营养物质匮乏条件下蛋白质动态降解的过程,自噬性细胞死亡是不同于细胞凋亡的另一种细胞程序性死亡模式,被称之为II型程序性死亡,细胞凋亡为I型程序性死亡。研究表明,肿瘤的发生发展与自噬性细胞死亡相关,作为肿瘤抑制基因p53也参与了自噬活性的调节。本文对此做一简要概述。     

细胞自噬及其在肿瘤发生过程中的作用

细胞自噬性死亡是一种非凋亡性的程序性细胞死亡,其特征是在垂死细胞中利用自噬小体对细胞内容物进行降解。现对自噬的病理形态特征、生化改变、发生机制、分子调控、与凋亡的联系进行综述,以利于加深对细胞死亡方式的进一步认识,并介绍自噬在肿瘤发生过程中作用的研究进展。     

细胞自噬及其在肿瘤发生过程中的作用

细胞自噬性死亡是一种非凋亡性的程序性细胞死亡，其特征是在垂死细胞中利用自噬小体对细胞内容物进行降解。现对自噬的病理形态特征、生化改变、发生机制、分子调控、与凋亡的联系进行综述，以利于加深对细胞死亡方式的进一步认识，并介绍自噬在肿瘤发生过程中作用的研究进展。     

自噬与凋亡的相互关系在肿瘤方面的研究进展

肿瘤是一类涉及基因、代谢和信号传导异常等多方面因素引起的疾病,其发生的分子机制相当复杂,但本质上仍与细胞增殖与死亡的动态失衡有关。程序性细胞死亡（programmed cell death,PCD）是由基因控制的自杀程序引起的主动性死亡,对于多细胞生物个体发育的正常进行,维持内环境稳态以及抵御外界各种干扰因素方面有着关键性的意义。I型PCD（经典细胞凋亡）和II型PCD（自噬性细胞死亡）调控着肿瘤细胞的增殖与消耗,与肿瘤的发生、发展密切相关。本文结合近年来国内外研究进展,重点就自噬在肿瘤中的作用以及与凋亡的相互关系作一综述。     

自噬在细胞铁死亡发生中作用机制的研究进展

铁死亡（ferroptosis）是近年来新发现的一种非凋亡性细胞程序性死亡方式,以铁依赖性和脂质活性氧(lipid reactive oxygen species,L-ROS)累积为特征。自噬是真核生物中的高度保守的生物代谢过程,广泛参与机体生物调节。研究发现细胞铁死亡与自噬在肿瘤发生发展中关系密切,自噬调控基因及相关信号通路与铁死亡过程发生交互调节,影响细胞死亡进程。本文将概述铁死亡与自噬的发生及调节机制,综述自噬在铁死亡发生过程中的作用,展望利用自噬与铁死亡的相互作用对肿瘤治疗的意义。     

p53 基因相关的细胞非经典死亡

[摘要] 程序性细胞死亡是多细胞生物死亡的重要生物学过程,其调控方式复杂,对维持细胞内环境稳定十分重要。在过去的几年中,除了凋亡之外,对程序性细胞死亡的非凋亡形式的研究也取得了进展。p53 作为经典的肿瘤抑制因子,除了控制细胞增殖和凋亡外,也参与非典型细胞死亡调控。p53 通过对其下游靶点的转录调控以及与关键蛋白的直接作用,直接或间接调节细胞的非典型死亡。本文对p53 在凋亡、铁中毒、细胞程序性坏死、自噬性细胞死亡、有丝分裂灾难、副凋亡等几种非典型细胞死亡模式中的作用作一综述,为肿瘤抑制机制的阐明及癌症药物研制提供相应参考。     

肝细胞程序性坏死的研究进展

程序性坏死作为一种新发现的受信号分子调控的细胞死亡方式,参与多种疾病的发生和发展过程。与通常认为的坏死、凋亡和自噬不同,程序性坏死具有特异的分子机制,且其信号通路中的相关分子正成为人们研究的热点。近期有研究表明,程序性坏死均参与急性或慢性肝损伤、肝纤维化等过程,并与肝脏炎性疾病的发生发展有着密切的关系。因此,本文就程序性坏死的分子机制及其与肝细胞死亡的关系进行综述,为预防多种形式的肝损伤和治疗肝脏疾病提供新的思路。     

不同类型程序性细胞死亡途径在肾癌中的研究进展

程序性细胞死亡（PCD）是机体内由遗传基因决定的细胞主动、有序的死亡方式，它在机体进化、维持机体稳态以及多个组织器官的发育中发挥重要作用，而这一过程的调控异常还与包括癌症在内的多种人类疾病密切相关。目前发现的PCD途径有细胞凋亡、自噬、坏死性凋亡、细胞焦亡和铁死亡，这些途径可在细胞受到各种内外部环境因素的刺激时被激活。研究表明，这些途径可以在多种信号分子的调控下诱导肾癌细胞死亡或维持细胞存活，从而影响肿瘤的进展或治疗效果。本文结合近年来的研究进展，针对以上多种PCD途径在肾癌发生发展中的作用进行综述，以期为深入研究肾癌的发病机制以及研发抗肿瘤靶向药物提供新方向。     

自噬在乳腺癌中作用的研究进展

细胞自噬是一种广泛存在于真核生物中的细胞程序性死亡机制,能够在细胞生长过程中维持细胞能量的平衡并且对养分胁迫产生应答反应。白噬在清除受损细胞器,如线粒体、内质网、过氧化物酶等以及消灭病原体的过程中起到重要作用。自噬不但在细胞增殖的早期起到保护性作用,在细胞死亡过程中,也起到重要的作用。研究发现自噬活性的变化,与肿瘤的发生、神经变性、微生物感染以及老龄化有关。自噬性细胞死亡与乳腺肿瘤的发生、发展有关。本文就自噬发生的机制以及其在乳腺癌发生发展中作用的研究进展进行综述。     

Autophagy as a cell death and tumor suppressor mechanism

Autophagy is characterized by sequestration of bulk cytoplasm and organelles in double or multimembrane autophagic vesicles, and their delivery to and subsequent degradation by the cell's own lysosomal system. Autophagy has multiple physiological functions in multicellular organisms, including protein degradation and organelle turnover. Genes and proteins that constitute the basic machinery of the autophagic process were first identified in the yeast system and some of their mammalian orthologues have been characterized as well. Increasing lines of evidence indicate that these molecular mechanisms may be recruited by an alternative, caspase-independent form of programmed cell death, named autophagic type II cell death. In some settings, autophagy and apoptosis seem to be interconnected positively or negatively, introducing the concept of 'molecular switches' between them. Additionally, mitochondria may be central organelles integrating the two types of cell death. Malignant transformation is frequently associated with suppression of autophagy. The recent implication of tumor suppressors like Beclin 1, DAP-kinase and PTEN in autophagic pathways indicates a causative role for autophagy deficiencies in cancer formation. Autophagic cell death induction by some anticancer agents underlines the potential utility of its induction as a new cancer treatment modality.     

Autophagic tumor stroma: Mechanisms and roles in tumor growth and progression

Macroautophagy (hereafter autophagy) is a cellular homeostatic mechanism that involves protein and organelle degradation, and has a number of connections to human physiology and diseases. Autophagy in tumor parenchyma acts as either a tumor‐promoting role or a tumor‐inhibiting role depending on the types and stages of tumors. In recent years, attention to autophagy in tumor stroma that is referred as “autophagic tumor stroma” has created a new paradigm to understand the role of autophagy in cancer. Here we propose that the autophagic tumor stroma is a phenomenon of adaptation at a certain stage of tumor development, and has a prominent role in tumor growth, progression and spread of tumors. This idea is supported by recent studies: (i) Autophagic tumor stroma is activated by hypoxia and cancer cells induced oxidative stress, when tumors grow to a certain stage; (ii) Autophagic tumor stroma aids in providing essential nutrients to malignant cells, remodeling the tumor microenvironment, increasing DNA damage, genetic instability and stemness in cancer cells, and decreasing the apoptotic sensitivity of cancer cells. The autophagic tumor stroma is therefore a significant determinant in tumor growth and progression and implicates an important target for cancer therapies.     

Caspase-mediated cleavage of ATG6/Beclin-1 links apoptosis to autophagy in HeLa cells

Autophagy is a catabolic process involved in cell death and in cell protective mechanism. Autophagic cell death is differentiated from apoptosis by the presence of double or multiple-membrane enclosed vesicles, and the ATG proteins are essential for the formation of these autophagic vesicles. Here, we show that ATG6/Beclin-1 is a novel caspase substrate. ATG6 is directly cleaved by caspases in a process inhibited by the pan caspase inhibitor, zVAD. Ectopic expression of ATG6 suppresses cell death while reduction of ATG6 levels by siRNA sensitizes cells to TRAIL-induced cell death. Also, the inhibition of caspases leads to an increase in autophagy. These results suggest that caspase-mediated cleavage of ATG6 links the apoptotic and autophagic signaling pathways.     

自噬在恶性肿瘤治疗中的进展及影像学应用前景

自噬是在营养缺乏条件下维持细胞代谢的主要途径。这使其成为肿瘤研究的新热点,调控自噬信号通路的机制已经很明确,越来越多的研究发现机体细胞自噬活性变化对肿瘤治疗的效果具有巨大影响。但缺乏能够重复比较或靶向定位自噬活性的测量技术。正电子示踪剂PET等影像手段通过将相关自噬的信号通路蛋白标记放射性核素进行显像似乎具有解决这些问题的潜力。在本文中,我们综述自噬在肿瘤治疗中的应用,并展望医学影像技术协助自噬治疗肿瘤的前景。     

Targeting autophagic pathways for cancer drug discovery

Autophagy , an evolutionarily conserved lysosomal degradation process , has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer. To date, substantial evidence has demonstrated that some key autophagic mediators, such as autophagy-related genes (ATGs), PI3K, mTOR, p53, and Beclin-1, may play crucial roles in modulating autophagic activity in cancer initiation and progression. Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer, it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics. With a deeper understanding of the regulatory mechanisms governing autophagy, we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer. This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.     

Autophagy and cancer therapy

Although autophagy has been shown to have a clear role as a tumor suppressor mechanism, its role in cancer treatment is still controversial. Because autophagy is a survival pathway activated during nutrient deprivation and other stresses, it is reasonable to think that autophagy can function as a tumor cell survival mechanism activated after cancer treatment. Such a mechanism could be widely important because most cancer treatments induce autophagy in tumor cells. Indeed, many papers have presented data suggesting that tumor cell autophagy induced by anti-cancer treatment inhibits tumor cell killing. However, it has also been proposed that autophagy is a cell death mechanism that could function as a backup when apoptosis is disabled. The fact that there are active clinical trials in patients both using autophagy inhibitors or inducers together with other cancer treatments underscores the importance of understanding and distinguishing between these opposing ideas. Here we discuss some of the recent work studying the role of autophagy with different cancer therapies.     

自噬在胃癌中的研究进展

近年来，自噬在胃癌中的作用得到了广泛的关注，自噬犹如一把“双刃剑”在肿瘤发展过程中扮演重要的双面角色，对肿瘤的发展既有抑制作用，又有促进作用，本文对自噬抑制胃癌早期的形成以及促进中晚期胃癌的药物抗性等最新研究进展进行介绍。探讨细胞自噬与胃癌的关系，有助于深入了解胃癌的发生发展以及预后等一系列问题，希望为胃癌的早期诊断和诊治提供新的治疗途径。     

Autophagic cell death induced by 5-FU in Bax or PUMA deficient human colon cancer cell

Autophagy is a membrane process that results in the transporting of cellular contents to lysosomes for degradation. Autophagic cell death is another way of programed cell death called type II PCD, which has complicated connection with apoptosis, both of these two types of cell death play an important role in tumor development. In this study, we investigated chemotherapeutic agent induced cell death pathway in wild type (WT), Bax^−/− and PUMA^−/− HCT116 cells. Bax or PUMA deficient cells had similar chemosensitivity to WT cells but were defective in undergoing apoptosis. The results of electron microscopy and GFP–LC3 localization assay showed that autophagy was induced in Bax or PUMA deficient cells but not in WT cells. mTOR activity was decreased in Bax or PUMA deficient cells which further indicated the up-regulation of autophagy. Inhibition of autophagy by 3-Methyladenine (3-MA) decreased the cell death in Bax or PUMA deficient cells. Taken together, these results suggest that autophagic cell death can be used as an alternative cell death pathway in apoptosis defective cells and may bring a new target for cancer therapy.