Autophagy: The spotlight for cellular stress responses

Frontiers in Cell and Developmental Biology, 2018

Growing amount of evidence in the last two decades highlight that macroautophagy (generally referred to as autophagy) is not only indispensable for survival in yeast but also equally important to maintain cellular quality control in higher eukaryotes as well. Importantly, dysfunctional autophagy has been explicitly shown to be involved in various physiological and pathological conditions such as cell death, cancer, neurodegenerative, and other diseases. Therefore, modulation and regulation of the autophagy pathway has emerged as an alternative strategy for the treatment of various disease conditions in the recent years. Several studies have shown genetic or pharmacological modulation of autophagy to be effective in treating cancer, clearing intracellular aggregates and pathogens. Understanding and controlling the autophagic flux, either through a genetic or pharmacological approach is therefore a highly promising approach and of great scientific interest as spatiotemporal and cell-tissue-organ level autophagy regulation is not clearly understood. Indeed, chemical biology approaches that identify small molecule effectors of autophagy have thus a dual benefit: the modulators act as tools to study and understand the process of autophagy, and may also have therapeutic potential. In this review, we discuss different strategies that have appeared to screen and identify potent small molecule modulators of autophagy.

Pharmacological research, 2016

Autophagy is an evolutionarily conserved cellular degradative process in which intracellular components (cellular proteins and organelles) are engulfed in autophagosomes which then fuse with lysosomes to form autolysosome for degradation. Autophagy is closely implicated in various physio-pathological processes and human diseases. Among them, the roles of autophagy in cancer have been extensively studied. Increasing evidence has demonstrated that inhibiting autophagy is a novel and promising approach in cancer therapy, based on the notion that autophagy is a pro-survival mechanism in cancer cells under therapeutic stress, and induction of autophagy is associated with chemoresistance of cancer cells to chemotherapeutic agents. Thus, suppression of autophagy would sensitize resistance tumor cells to cancer therapeutic agents, thereby supporting the clinical application of autophagy inhibitors. In recent years, significant progress has been achieved in developing autophagy inhibitors an...

Cancers

Autophagy is an important cellular repair mechanism, aiming at sequestering misfolded and dysfunctional proteins and damaged cell organelles. Dysfunctions in the autophagy process have been linked to several diseases, like infectious and neurodegenerative diseases, type II diabetes mellitus and cancer. Living organisms are constantly subjected to some degree of oxidative stress, mainly induced by reactive oxygen and nitrogen species. It has been shown that autophagy is readily induced by reactive oxygen species (ROS) upon nutrient deprivation. In recent years, research has increasingly focused on outlining novel therapeutic targets related to the autophagy process. With this review of the literature, we want to give an overview about the link between autophagy, oxidative stress and carcinogenesis.

Autophagy, 2015

Autophagy and inflammation are 2 fundamental biological processes involved in both physiological and pathological conditions. Through its crucial role in maintaining cellular homeostasis, autophagy is involved in modulation of cell metabolism, cell survival, and host defense. Defective autophagy is associated with pathological conditions such as cancer, autoimmune disease, neurodegenerative disease, and senescence. Inflammation represents a crucial line of defense against microorganisms and other pathogens, and there is increasing evidence that autophagy has important effects on the induction and modulation of the inflammatory reaction; understanding the balance between these 2 processes may point to important possibilities for therapeutic targeting. This review focuses on the crosstalk between autophagy and inflammation as an emerging field with major implications for understanding the host defense on the one hand, and for the pathogenesis and treatment of immune-mediated diseases on the other hand.

AJP: Cell Physiology, 2010

The autophagosome is the central organelle in macroautophagy, a vacuolar lysosomal catabolic pathway by which cytoplasmic material is degraded to fuel cells subjected to starvation, via which intracellular pathogens are eliminated. Macroautophagy plays important physiological roles during development, ageing, and the immune response, and the cytoprotective function of macroautophagy is compromised in diseases such as cancer, neurodegenerative disorders, and diabetes. A set of autophagy-related (ATG) proteins is hierarchically recruited to the phagophore, the initial membrane template in the construction of the autophagosome. However, recent findings suggest that macroautophagy can also occur without some of these key autophagy proteins, and such alternatives to the evolutionarily-conserved scheme might provide additional opportunities for therapeutic intervention.

Molecular Cancer Therapeutics, 2011

Autophagy is a homeostatic, catabolic degradation process whereby cellular proteins and organelles are engulfed into autophagosomes, digested in lysosomes and recycled to sustain cellular metabolism. Autophagy has dual roles in cancer, acting as both a tumor suppressor by preventing the accumulation of damaged proteins and organelles and as a mechanism of cell survival that can promote the growth of established tumors. Tumor cells activate autophagy in response to cellular stress including hypoxia and increased metabolic demands related to rapid cell proliferation. Autophagy-related stress tolerance can enable cell survival by maintaining energy production that can lead to tumor growth and therapeutic resistance, as shown in preclinical models where the inhibition of autophagy can restore chemosensitivity and enhance tumor cell death. These results established autophagy as a therapeutic target and have led to multiple early phase clinical trials in humans evaluating autophagy inhibition using hydroxychloroquine in combination with chemotherapy or targeted agents. Targeting autophagy in cancer provides new opportunities for drug development since more potent and specific inhibitors of autophagy are needed. The role of autophagy and its regulation in cancer cells continues to emerge and studies aim to define optimal strategies to modulate autophagy for therapeutic advantage.

Autophagy is a catabolic pathway of lysosomal re-cycling of cell constituens and xenobiotics by the mechanisms of sequestration of targeted biomolecules and compromised organelles within isolating membranes, i.e., autophagosomes, or protein complexes and processing them in lysosomal macinery. By this means autophagy mediates cell and organelle biogenesis, provides energy supplys and sustains systems integrity and homeostasis. Autophagy is evolutionary conserved and ubiquitouly present in eukaryotes, e.g., multicellular organisms such as fungi, plants and animals. Therefore, many details related to autophagy signaling, target-selection, autophagy flux, as well as autophagy-targeted modulation of cell and tissue biogenesis and morphogenesis have been recently investigated using in vitro models, everterbrates and lower vertebrate animals. Alsough, autolysosomal process per se is still considered to be a bulk hydrolytic degradation, a growing number of evidence indicate that autophagy biogenesis is strictly regulated by autophagy-related genes (i.e., ATG genes) and their protein products, numerous signaling cascades, adaptors, chaperones, modifiers, cell energetic conditions, and intimate interactions in the organelle networks (e.g., the endoplasmic reticulum - mitocondrial interplay). Overall, that determine cargo-selictivity to proteins and organelles as well as the pathway specificity (e.g., macroautophagy vs. chaperone-mediated autophagy). This network governs a crucial autophagy feature which is execution of barrier functions by targeting, sequestration and compartmentalisation for recycling of damaged cytotoxic constituents, acquired xenobiotics and invading pathogens. These barrier functions “arms” organisms with ability to specifically respond to starvation, oxidative, electrophilic and hypoxia stress related to acute injury and hyperinflammation; as well as to mediate innate and adaptive immunity and to control aging, infections, degenerative disease, cancer development, etc. Remarkably, the interplay between autophagy biogenesis and the endoplasmic reticulum-mitochondrial axis, cell metabolome, proteostasis and energetic machinery defines capacity of cell intrinsing resistance to stress impacts and impairments. These evidence can imply novel concepts for therapy of numerous illnesses such as cystic fibrosis, preeclampsia, drug addiction-related disease, and disfunctions of heart, lung, and nervous tissue.

The EMBO Journal, 2021

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.

IAA Journal of Scientific Research, 2024

Autophagy, an evolutionarily conserved cellular process, intricately regulates the degradation and recycling of cellular components, ensuring cellular homeostasis. The molecular orchestration of autophagy involves a sophisticated network of signaling pathways and key molecular players. Key initiation steps involve nutrient-sensing pathways, including mTOR and AMPK, converging on the ULK1 complex, triggering autophagosome formation. Subsequent stages encompass the role of the PI3K complex, recruitment of ATGs, and autophagosome expansion, leading to cargo recognition and closure. The selectivity in autophagy is achieved through cargo-specific adaptors and receptors like p62/SQSTM1, NIX/BNIP3L, and NDP52, ensuring targeted degradation of damaged organelles, misfolded proteins, and pathogens. Upon fusion with lysosomes, autolysosomes are formed, culminating in the breakdown of engulfed cargo via lysosomal hydrolases. Autophagy's intricate interplay with cellular processes, including metabolism, immunity, and cell death pathways, underscores its multifaceted roles in physiological and pathological conditions. Dysregulated autophagy is implicated in neurodegenerative disorders, cancer, metabolic diseases, and infections, highlighting its clinical relevance. Understanding the molecular mechanisms of autophagy offers promising prospects for therapeutic interventions by targeting autophagic pathways. This overview provides insights into the molecular intricacies of autophagy, offering potential avenues for therapeutic modulation in various disease contexts.

Multidisciplinary Digital Publishing Institute-Diseases, 2019

Autophagy is a regular and substantial “clear-out process” that occurs within the cell and that gets rid of debris that accumulates in membrane-enclosed vacuoles by using enzyme-rich lysosomes, which are filled with acids that degrade the contents of the vacuoles. This machinery is well-connected with many prevalent diseases, including cancer, HIV, and Parkinson’s disease. Considering that autophagy is well-known for its significant connections with a number of well-known fatal diseases, a thorough knowledge of the current findings in the field is essential in developing therapies to control the progression rate of diseases. Thus, this review summarizes the critical events comprising autophagy in the cellular system and the significance of its key molecules in manifesting this pathway in various diseases for down-or upregulation. We collectively reviewed the role of autophagy in various diseases, mainly neurodegenerative diseases, cancer, inflammatory diseases, and renal disorders. Here, some collective reports on autophagy showed that this process might serve as a dual performer: either protector or contributor to certain diseases. The aim of this review is to help researchers to understand the role of autophagy-regulating genes encoding functional open reading frames (ORFs) and its connection with diseases, which will eventually drive better understanding of both the progression and suppression of different diseases at various stages. This review also focuses on certain novel therapeutic strategies which have been published in the recent years based on targeting autophagy key proteins and its interconnecting signaling cascades

Applied Microbiology and Biotechnology, 2014

Autophagy is a catabolic pathway that regulates homeostasis in cells. It is an exceptional pathway of membrane trafficking. Autophagy is characterized by the formation of double-membrane vesicles; autophagosomes that are responsible for delivering damaged organelle and extra proteins to lysosome for recycling. A series of actions including environmental and genetic factors are responsible for induction of autophagy. In the past few decades, the research on autophagy has been immensely expanded because it is a vital process in maintaining cellular balance as well as deeply connected with pathogenesis of a number of diseases. The aim of this review is to present an overview of modern work on autophagy and highlight some essential genetic role in the induction of autophagy. There is an emerging need to identify, quantify, and manipulate the pathway of autophagy, due to its close relationship with a variety of developmental pathways and functions especially in cancer, diabetes, neurodegenerative disorders, and infectious diseases.

American Journal of PharmTech Research, 2018

Autophagy is an intracellular 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 various diseases like Cancer, Neurodegenerative disease etc.

Antioxidants & Redox Signaling, 2014

Significance: The molecular machinery regulating autophagy has started becoming elucidated, and a number of studies have undertaken the task to determine the role of autophagy in cell fate determination within the context of human disease progression. Oxidative stress and redox signaling are also largely involved in the etiology of human diseases, where both survival and cell death signaling cascades have been reported to be modulated by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Recent Advances: To date, there is a good understanding of the signaling events regulating autophagy, as well as the signaling processes by which alterations in redox homeostasis are transduced to the activation/regulation of signaling cascades. However, very little is known about the molecular events linking them to the regulation of autophagy. This lack of information has hampered the understanding of the role of oxidative stress and autophagy in human disease progression. Critical Issues: In this review, we will focus on (i) the molecular mechanism by which ROS/RNS generation, redox signaling, and/or oxidative stress/damage alter autophagic flux rates; (ii) the role of autophagy as a cell death process or survival mechanism in response to oxidative stress; and (iii) alternative mechanisms by which autophagy-related signaling regulate mitochondrial function and antioxidant response. Future Directions: Our research efforts should now focus on understanding the molecular basis of events by which autophagy is fine tuned by oxidation/reduction events. This knowledge will enable us to understand the mechanisms by which oxidative stress and autophagy regulate human diseases such as cancer and neurodegenerative disorders. Antioxid. Redox Signal. 21, 66-85.

Cancers

Autophagy is a physiological cellular process that is crucial for development and can occurs in response to nutrient deprivation or metabolic disorders. Interestingly, autophagy plays a dual role in cancer cells—while in some situations, it has a cytoprotective effect that causes chemotherapy resistance, in others, it has a cytotoxic effect in which some compounds induce autophagy-mediated cell death. In this review, we summarize strategies aimed at autophagy for the treatment of cancer, including studies of drugs that can modulate autophagy-mediated resistance, and/or drugs that cause autophagy-mediated cancer cell death. In addition, the role of autophagy in the biology of cancer stem cells has also been discussed.

Revista de la Facultad de Medicina, 2016

Autophagy is an evolutionary process preserved in eukaryotes, which removes harmful components and maintains cell homeostasis in response to a variety of extracellular stimuli. It is involved in both physiological and pathological conditions, including cancer.The role of autophagy in the treatment of cancer is described as a “double-edged sword”, which reflects its involvement in tumor suppression, survival and subsequent proliferation of tumor cells. Recent advances are useful for planning appropriate adjustments to inhibit or promote autophagy in order to obtain therapeutic efficacy in cancer patients. The objectives of this review are to clarify the role of autophagy in cancer and to highlight the need for more research in the field.