Autophagy in tumor suppression and cancer therapy

Autophagy is a stress-induced cell survival program whereby cells under metabolic, proteotoxic, or other stress remove dysfunctional organelles and/or misfolded/polyubiquitylated proteins by shuttling them via specialized structures called autophagosomes to the lysosome for degradation. The end result is the release of free amino acids and metabolites for use in cell survival. For tumor cells, autophagy is a double-edged sword: autophagy genes are frequently mono-allelically deleted, silenced, or mutated in human tumors, resulting in an environment of increased oxidative stress that is conducive to DNA damage, genomic instability, and tumor progression. As such, autophagy is tumor suppressive. In contrast, it is important to note that although tumor cells have reduced levels of autophagy, they do not eliminate this pathway completely. Furthermore, the exposure of tumor cells to an environment of increased metabolic and other stresses renders them reliant on basal autophagy for survival. Therefore, autophagy inhibition is an active avenue for the identification of novel anti-cancer therapies. Not surprisingly, the field of autophagy and cancer has experienced an explosion of research in the past 10 years. This review covers the basic mechanisms of autophagy, discusses its role in tumor suppression and cancer therapy, and posits emerging questions for the future.     

Autofagia – proces o dwóch obliczach

Autophagy is a process that is involved in the pathogenesis of cancer but also in the development of resistance or sensitivity to cytostatic treatment applied.Until now, the issue is still unresolved if we should stimulate or inhibit the process of autophagy in cancer treatment through the use of appropriate anticancer therapy so that it is beneficial for the patient and induce remission of the disease. On the one hand autophagy as a mechanism of programmed cell death may also cause the death of tumor cells. On the other hand, as a defense mechanism is the process of cell survival strategy in stress situations such as hypoxia in the peripheral parts of the tumor or using cytostatic drugs.It would be good to find an answer if the autophagy is the process increasing the effectiveness of therapy or increasing resistance to treatment in a case of specific tumor.     

Autophagy in the immune system

Autophagy is an intracellular homeostatic mechanism important for the degradation of waste components from the cytoplasm in acidic lysosomal compartments. Originally, surplus parts of the cytoplasm that acted as targets for autophagy were thought to comprise cellular organelles and proteins, but this has now extended to include a range of pathogens with particular emphasis on intracellular bacteria. The finding that autophagy can sequester intracellular bacteria and mediate their destruction has opened the door to a wider role for autophagy as an effector arm of the immune system. In innate immunity, autophagy works downstream of pattern recognition receptors where it facilitates a number of effector responses, including cytokine production and phagocytosis. Autophagy is also able to intersect pathways of innate and adaptive immunity through its potential to deliver antigens for antigen presentation. Autophagy provides a substantial source of antigens for loading onto MHC class II molecules and it may be important in dendritic cells for cross‐priming to CD8⁺ T cells. In lymphocytes, autophagy is essential for cell survival and homeostasis, particularly in T cells. In the thymus, autophagy can modulate the selection of certain CD4⁺ T‐cell clones while in the bone marrow autophagy is needed for B‐cell development at specific stages. However, large holes exist in our knowledge as to how autophagy regulates, and is regulated by, the immune system and it is important to now apply what we have gleaned from in vitro studies to how autophagy operates in vivo in the setting of natural infection.     

Autophagy and Tumorigenesis

Autophagy, a catabolic process involved in the sequestration and lysosomal degradation of cytoplasmic contents, is crucial for cellular homeostasis. The current literature supports that autophagy plays diverse roles in the development, maintenance, and progression of tumors. While genetic evidence indicates autophagy functions as a tumor suppressor mechanism, it is also apparent that autophagy can promote the survival of established tumors under stress conditions and in response to chemotherapy. In this review, we discuss the mechanisms and the evidence underlying these multifaceted roles of autophagy in tumorigenesis, the prospects for targeting autophagy in cancer therapy, and overview the potential markers that may be utilized to reliably detect autophagy in clinical settings.     

Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis

Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. Autophagy is also a haploinsufficient tumor suppressor mechanism for mammary tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in breast carcinomas. However, the mechanism by which autophagy suppresses breast cancer remains elusive. Here we show that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to metabolic stress and accelerated lumen formation in mammary acini. Autophagy defects also activated the DNA damage response in vitro and in mammary tumors in vivo, promoted gene amplification, and synergized with defective apoptosis to promote mammary tumorigenesis. Therefore, we propose that autophagy limits metabolic stress to protect the genome, and that defective autophagy increases DNA damage and genomic instability that ultimately facilitate breast cancer progression.     

Autophagy and inflammasomes

Autophagy is a ubiquitous cellular mechanism for the targeted lysosomal degradation of various cytosolic constituents, from proteins to organelles. As an essential homeostatic mechanism, autophagy is upregulated in response to numerous environmental and pharmacological stimuli, including starvation, where it facilitates the recycling of essential amino acids. In addition, autophagy plays specific roles within the immune system; it serves as a source of peptides for antigen presentation, a mechanism for the engulfment and degradation of intracellular pathogens and as a key regulator of inflammatory cytokines. In particular, autophagy has been shown to play a number of roles in regulating inflammasome activation, from the removal of inflammasome-activating endogenous signals, to the sequestration and degradation of inflammasome components. Autophagy also plays a role in determining the fate of IL-1β, which is concentrated in autophagosomes. This review discusses a growing body of literature that suggests autophagy is a critical regulator of inflammasome activation and the subsequent release of IL-1 family cytokines.     

Autophagy in arsenic carcinogenesis

Chronic exposure to arsenic may cause cancer. Many mechanisms have been suggested for arsenic carcinogenesis. Autophagy, an evolutionarily conserved cellular catabolic mechanism, has been implicated in cancer biology. Although being claimed as a type of cell death, autophagy may actually serve as a cell self-defense mechanism. In this review article, current understandings of the mechanisms of arsenic carcinogenesis, functions of autophagy and the role of autophagy in arsenic carcinogenesis are discussed.     

Autophagy in clear cell ovarian cancer,a potential marker for hypoxia and poor prognosis?#

Autophagy contributes to cell survival and is up‐regulated under hypoxia in many different cancers. Ovarian cancer has a poor prognosis and is generally resistant to chemotherapy. Through genetic profiling, it has becoming evident that ovarian cancer has distinct subtypes but the significance of these subtypes in ovarian cancer remains unclear. In this issue, Dr Lum and colleagues have presented evidence that autophagy as measured by LC3A staining occurs in a clear cell ovarian cancer that is correlated with hypoxic regions and poor overall survival. In addition, autophagy under hypoxia appears to be higher in clear cell ovarian cancer cells compared to other subtypes. This indicates that autophagy could be a factor in drug resistance and poor survival in clear cell ovarian cancer patients. This insight could lead to a better understanding of the role of autophagy under hypoxia in human ovarian cancer and could be a valuable biomarker for the development of better therapies for clear cell ovarian cancers. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

自噬与固有免疫应答相互调节研究进展

自噬在细胞分化、肿瘤、炎症、免疫等多方面发挥关键作用.近年来,随着分子生物学、细胞生物学、免疫学等学科的发展,研究发现细胞自噬与固有免疫应答有着重要的相互调控作用.自噬是固有免疫的重要组成成分,可以通过溶酶体直接降解被自噬体包裹的病原体.自噬参与众多固有免疫信号的调控.固有免疫信号也诱导或抑制自噬.自噬在抗胞内病原体感染中发挥重要作用.     

Autophagy: cellular and molecular mechanisms

Autophagy is a self‐degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non‐apoptotic cell death. Autophagy can be either non‐selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. This review summarizes the most up‐to‐date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Autophagy suppresses tumor progression by limiting chromosomal instability

Autophagy is a bulk degradation process that promotes survival under metabolic stress, but it can also be a means of cell death if executed to completion. Monoallelic loss of the essential autophagy gene beclin1 causes susceptibility to metabolic stress, but also promotes tumorigenesis. This raises the paradox that the loss of a survival pathway enhances tumor growth, where the exact mechanism is not known. Here, we show that compromised autophagy promoted chromosome instability. Failure to sustain metabolism through autophagy was associated with increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis. Thus, autophagy maintains metabolism and survival during metabolic stress that serves to protect the genome, providing an explanation for how the loss of a survival pathway leads to tumor progression. Identification of this novel role of autophagy may be important for rational chemotherapy and therapeutic exploitation of autophagy inducers as potential chemopreventive agents.     

Autophagy as an immune defense mechanism

Autophagy is a homeostatic process whereby cytosol or intracellular organelles are sequestered by a double membrane structure termed autophagosome for subsequent delivery to lysosomes and degradation. Autophagy takes part in cell survival and death and has been implicated in development, aging, neurodegeneration and cancer. The newly discovered specialized role of autophagy in immune cells expands autophagic functions to defense against intracellular pathogens. Furthermore, autophagy is involved in acquired immunity, such as antigen processing for MHC II presentation, and is modulated by cytokines such as IFN-gamma. A further link has emerged between autophagy and defense against intracellular pathogens via the immunity-related GTPase lrgm1 (LRG-47), which has a protective role against Mycobacterium tuberculosis. We propose the term immunophagy for these defense processes.     

中药诱导肿瘤细胞自噬及其分子机制

自噬是细胞膜结构吞噬自身的细胞质形成自噬体,并与溶酶体结合对细胞内蛋白质和细胞器降解的过程。自噬参与细胞诸多生理和病理过程,其与肿瘤发生密切相关。近年来对细胞自噬在肿瘤中的作用及其作为抗肿瘤药物的作用机制的研究有了较大进展,特别是某些中药及有效成分如姜黄素、苦参碱、雷公藤内酯等能诱导肿瘤细胞自噬,自噬将成为肿瘤研究的一个新热点。现将自噬的分子机制、自噬与肿瘤、中药诱导肿瘤细胞自噬及其分子机制的研究进展做一综述。     

AMPK-mTOR-ULK1/2信号通路与自噬

自噬(autophagy)又称Ⅱ型细胞死亡,是细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程.研究发现,自噬与多种疾病的发生发展密切相关,包括阿尔兹海默症、心肌病、肿瘤.AMPK-mTOR-ULK1/2信号通路对自噬具有重要的调控作用,对该通路的深入研究将有助于更好地理解细胞自噬过程,并为自噬相关疾病的治疗提供新的靶点.该文总结了AMPK-mTOR-ULK1/2信号通路中各分子的作用及其对自噬的调控机制及相关研究进展.     

结核病免疫应答中自噬现象的分子机制和意义

越来越多的证据表明,自噬是结核免疫反应的重要组成部分.自噬可以杀灭结核分枝杆菌、调节促炎细胞因子的分泌、增加抗原递呈功能.自噬与其他抗菌途径如维生素D3、炎性体、泛素系统存在协同作用.另一方面,结核分枝杆菌可以调控巨噬细胞的自噬.目前,自噬已成为临床重要的诊疗靶点.其能诱导自噬的药物,可以作为佐剂治疗耐药性结核;能有效诱导自噬的疫苗,可能提供更好的免疫保护作用.     

自噬在免疫及免疫相关疾病中的研究进展

自噬是细胞内溶酶体/内体参与的,涉及细胞增殖,分化及稳态平衡调节的降解过程.遗传学研究发现其在物种进化过程中较保守,从酵母到哺乳动物细胞中均有自噬相关基因的存在,提示自噬广泛参与各类生物正常的生理过程.近年来,随着研究的不断深入,人们发现自噬在许多疾病尤其在免疫相关疾病中亦扮演着重要角色,在感染,自身免疫,肿瘤免疫中所起的作用可为今后研究提供依据.     

Autophagy and antiviral immunity

Autophagy is an ancient pathway designed to maintain cellular homeostasis by degrading long-lived proteins and organelles in the cytosol. Recent studies demonstrate that autophagy is utilized by the cells of the innate and adaptive immune systems to combat viral infections. Autophagy plays a key role in recognizing signatures of viral infection, and represents a critical effector mechanism to restrict viral replication. On the other hand, autophagosomes have been exploited by certain viruses as a niche for viral replication. Furthermore, autophagy can be used to deliver endogenous viral antigens to the MHC class II loading compartment, allowing activation of CD4 T cells. In this review, we describe recent advances in the field of autophagy as it relates to innate and adaptive antiviral immune responses.     

Induction of ROS, mitochondrial damage and autophagy in lung epithelial cancer cells by iron oxide nanoparticles

Autophagy has attracted a great deal of research interest in tumor therapy in recent years. An attempt was made in this direction and now we report that iron oxide NPs synthesized by us selectively induce autophagy in cancer cells (A549) and not in normal cells (IMR-90). It was also noteworthy that autophagy correlated with ROS production as well as mitochondrial damage. Protection of NAC against ROS clearly suggested the implication of ROS in hyper-activation of autophagy and cell death. Pre-treatment of cancer cells with 3-MA also exhibited protection against autophagy and promote cellular viability. Results also showed involvement of classical mTOR pathway in autophagy induction by iron oxide NPs in A549 cells. Our results had shown that bare iron oxide NPs are significantly cytotoxic to human cancer cells (A549) but not to the normal human lung fibroblast cells (IMR-90).In other words our nanoparticles selectively kill cancerous cells. It is encouraging to conclude that iron oxide NPs bear the potential of its applications in biomedicine, such as tumor therapy specifically by inducing autophagy mediated cell death of cancer cells.     

Autophagy dysregulation in amyotrophic lateral sclerosis

Autophagy is an intracellular lysosomal degradation process, which plays an important role in cell growth and development, and keeping cellular homeostasis in all eukaryotes. Autophagy has multiple physiological functions, including protein degradation, organelle turnover and response to stress. Emerging evidences support the notion that dysregulation of autophagy might be critical for pathogenesis of amyotrophic lateral sclerosis (ALS). The autophagy dysregulation in motor neurons of ALS may occur in different steps of the autophagic process. Recent studies have shown that two ALS associated proteins, TDP-43 and superoxide dismutase 1 (SOD1), are involved in the abnormal autophagy regulation. Furthermore, it is reported that several genetic mutations in ALS disturb the autophagic process in the motor neurons. This review will provide new evidence of autophagy dysregulation as a critical pathogenic process leading to ALS, and will discuss the prospect of future therapeutic targets using autophagic regulation to treat this disease.