The dynamic nature of autophagy in cancer

Macroautophagy (referred to hereafter as autophagy) is a highly regulated cellular process that serves to remove damaged proteins and organelles from the cell. Autophagy contributes to an array of normal and pathological processes, and has recently emerged as a key regulator of multiple aspects of cancer biology. The role of autophagy in cancer is complex and is likely dependent on tumor type, stage, and genetic context. This complexity is illustrated by the identification of settings where autophagy acts potently to either promote or inhibit tumorigenesis. In this review, I discuss the underlying basis for these opposing functions and propose a model suggesting a dynamic role for autophagy in malignancy. Collectively, the data point to autophagy as serving as a barrier to limit tumor initiation. Once neoplastic lesions are established, it appears that adaptive changes occur that now result in positive roles for autophagy in malignant progression and in subsequent tumor maintenance. Remarkably, constitutive activation of autophagy is critical for continued growth of some tumors, serving to both reduce oxidative stress and provide key intermediates to sustain cell metabolism. Autophagy is also induced in response to cancer therapies where it can function as a survival mechanism that limits drug efficacy. These findings have inspired significant interest in applying anti-autophagy therapies as an entirely new approach to cancer treatment. It is now apparent that aberrant control of autophagy is among the key hallmarks of cancer. While much needs to be learned about the regulation and context-dependent biological functions of autophagy, it seems clear that modulation of this process will be an attractive avenue for future cancer therapeutic approaches.     

Autophagy in Plasma Cell Ontogeny and Malignancy

Autophagy is a highly conserved pathway that recycles cytosolic material and organelles via lysosomal degradation. Once simplistically viewed as a non-selective survival strategy in dire straits, autophagy has emerged as a tightly regulated process ensuring organelle function, proteome plasticity, cell differentiation and tissue homeostasis, with key roles in physiology and disease. Selective target recognition, mediated by specific adapter proteins, enables autophagy to orchestrate highly specialized functions in innate and adaptive immunity. Among them, the shaping of plasma cells for sustainable antibody production through a negative control on their differentiation program. Moreover, memory B cells and long-lived plasma cells require autophagy to exist. Further, the plasma cell malignancy, multiple myeloma deploys abundant autophagy, essential for homeostasis, survival and drug resistance.     

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.     

Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment

Reactive oxygen species (ROS) have been identified as signaling molecules in various pathways regulating both cell survival and cell death. Autophagy, a self-digestion process that degrades intracellular structures in response to stress, such as nutrient starvation, is also involved in both cell survival and cell death. Alterations in both ROS and autophagy regulation contribute to cancer initiation and progression, and both are targets for developing therapies to induce cell death selectively in cancer cells. Many stimuli that induce ROS generation also induce autophagy, including nutrient starvation, mitochondrial toxins, hypoxia, and oxidative stress. Some of these stimuli are under clinical investigation as cancer treatments, such as 2-methoxyestrodial and arsenic trioxide. Recently, it was demonstrated that ROS can induce autophagy through several distinct mechanisms involving Atg4, catalase, and the mitochondrial electron transport chain (mETC). This leads to both cell-survival and cell-death responses and could be selective toward cancer cells. In this review, we give an overview of the roles ROS and autophagy play in cell survival and cell death, and their importance to cancer. Furthermore, we describe how autophagy is mediated by ROS and the implications of this regulation to cancer treatments.     

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 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.     

Selective degradation of p62 by autophagy

The autophagy–lysosome pathway is a highly conserved bulk degradation system in eukaryotes. During starvation, cytoplasmic constituents are non-selectively degraded by autophagy, and the resulting amino acids are utilized for cell survival. By taking advantage of mouse genetics, many physiological functions of mammalian autophagy have been uncovered. Growing lines of evidences have revealed the essential role of constitutive (or basal) autophagy in cellular homeostasis through its selectivity. p62, one of the selective substrates for autophagy, plays a key role in the formation of cytoplasmic proteinaceous inclusion, a hallmark of conformational diseases such as Alzheimer’s disease, Parkinson’s disease, and various chronic liver disorders. In this review, we discuss the physiological roles of the selective turnover of p62 by autophagy and their molecular mechanisms.     

Which roles for autophagy in Toxoplasma gondii and related apicomplexan parasites?

Autophagy is a life-sustaining process by which cytoplasmic components are sequestered in double-membrane vesicles called autophagosomes, and degraded after fusion with a lytic compartment. This process can be triggered under cellular stress conditions in order to recycle damaged organelles or provide nutrients to the cell, but may also be involved in cell remodelling during normal development. This catabolic process is conserved among most eukaryotes and characterisation of its molecular machinery has benefited greatly from functional genetic studies in yeast and mammalian models. Until recently, not much was known about the functions of autophagy in Apicomplexa, but recent data obtained in Toxoplasma have shed light on a very important role for this machinery, potentially at the crossroads between life and death decisions for the parasite. The possible roles for autophagy during the life cycles of other medically important apicomplexan parasites and the perspectives for discovering new drug targets in this pathway for combating these parasites are discussed in this review.     

Autophagy: from basic science to clinical application

Autophagy is a cellular pathway involved in protein and organelle degradation, which is likely to represent an innate adaptation to starvation. In times of nutrient deficiency, the cell can self-digest and recycle some nonessential components through nonselective autophagy, thus sustaining minimal growth requirements until a food source becomes available. Over recent years, autophagy has been implicated in an increasing number of clinical scenarios, notably infectious diseases, cancer, neurodegenerative diseases, and autoimmunity. The recent identification of the importance of autophagy genes in the genetic susceptibility to Crohn's disease suggests that a selective autophagic response may play a crucial role in the pathogenesis of common complex immune-mediated diseases. In this review, we discuss the autophagic mechanisms, their molecular regulation, and summarize their clinical relevance. This progress has led to great interest in the therapeutic potential of manipulation of both selective and nonselective autophagy in established disease.     

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.     

Dual role of autophagy in HIV-1 replication and pathogenesis

ABSTRACT: Autophagy, the major mechanism for degrading long-lived intracellular proteins and organelles, is essential for eukaryotic cell homeostasis. Autophagy also defends the cell against invasion by microorganisms and has important roles in innate and adaptive immunity. Increasingly evident is that HIV-1 replication is dependent on select components of autophagy. Fittingly, HIV-1 proteins are able to modulate autophagy to maximize virus production. At the same time, HIV-1 proteins appear to disrupt autophagy in uninfected cells, thereby contributing to CD4+ cell death and HIV-1 pathogenesis. These observations allow for new approaches for the treatment and possibly the prevention of HIV-1 infection. This review focuses on the relationship between autophagy and HIV-1 infection. Discussed is how autophagy plays dual roles in HIV-1 replication and HIV-1 disease progression.     

The role of autophagy in mediating cell survival and death during ischemia and reperfusion in the heart

Autophagy is a major mechanism for degrading long-lived cytosolic proteins and the only known pathway for degrading organelles. Autophagy is activated by many forms of stress, including nutrient and energy starvation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and infections. Although autophagy recycles amino acids and fatty acids to produce energy and removes damaged organelles, thereby playing an essential role in cell survival, inappropriate activation of autophagy leads to cell death. In the heart, activation of autophagy can be observed in response to nutrient starvation, ischemia/reperfusion, and heart failure. In this review, the signaling mechanism and the functional significance of autophagy during myocardial ischemia and reperfusion are discussed.     

缺氧状态下细胞自噬变化及其对心血管疾病的改善

自噬是细胞维持内环境稳态的重要方式之一,它是一种细胞缺血及代谢应激时与缺氧相关联的幸存机制。在某些心血管疾病中,缺血（缺氧）微环境会通过多种途径激活自噬,适当的自噬能够降解自身受损蛋白等来维持细胞生存,但当自噬过度时,则会损伤细胞,甚至使细胞发生II型程序性死亡。目前,治疗这类心血管疾病的方式主要有药物疗法和干细胞移植法,而白噬在这其中扮演着重要角色。对于不同类型和不同程度的心血管疾病,自噬可作为促存活机制,也可作为促死亡机制。因此,如何利用自噬有效改善某些心血管疾病是难点所在。     

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.     

Autophagy: process and function

Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Despite its simplicity, recent progress has demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles, which are sometimes complex. Autophagy consists of several sequential steps--sequestration, transport to lysosomes, degradation, and utilization of degradation products--and each step may exert different function. In this review, the process of autophagy is summarized, and the role of autophagy is discussed in a process-based manner.     

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.     

Viral interactions with macroautophagy: A double-edged sword

Autophagy is a conserved eukaryotic mechanism that mediates the removal of long-lived cytoplasmic macromolecules and damaged organelles via a lysosomal degradative pathway. Recently, a multitude of studies have reported that viral infections may have complex interconnections with the autophagic process. These observations strongly imply that autophagy has virus-specific roles relating to viral replication, host innate and adaptive immune responses, virus-induced cell death programs, and viral pathogenesis. Autophagy can supply internal membrane structures necessary for viral replication or may prolong cell survival during viral infections and postpone cell death. It can influence the survival of both infected and bystander cells. This process has also been linked to the recognition of viral signature molecules during innate immunity and has been suggested to help rid the cell of infection. This review discusses interactions between different viruses and the autophagy pathway, and surveys the current state of knowledge and emerging themes within this field.     

Autophagy in stem cell maintenance and differentiation

Autophagy is a lysosome-dependent degradation pathway that allows cells to recycle damaged or superfluous cytoplasmic content, such as proteins, organelles, and lipids. As a consequence of autophagy, the cells generate metabolic precursors for macromolecular biosynthesis or ATP generation. Deficiencies in this pathway were associated to several pathological conditions, such as neurodegenerative and cardiac diseases, cancer, and aging. The aim of this review is to summarize recent discoveries showing that autophagy also plays a critical role in stem cell maintenance and in a variety of cell differentiation processes. We also discuss a possible role for autophagy during cellular reprogramming and induced pluripotent stem (iPS) cell generation by taking advantage of ATP generation for chromatin remodeling enzyme activity and mitophagy. Finally, the significance of autophagy modulation is discussed in terms of augmenting efficiency of iPS cell generation and differentiation processes.     

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.