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Nature Reviews. Cancer Feb 2021Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several... (Review)
Review
Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours.
Topics: Animals; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Immunomodulation; Neoplasms; Neoplastic Processes; Signal Transduction; Tumor Microenvironment; Unfolded Protein Response
PubMed: 33214692
DOI: 10.1038/s41568-020-00312-2 -
Molecular Cell Apr 2022The endoplasmic reticulum (ER) is a hotspot for many essential cellular functions. The ER membrane is highly dynamic, which affects many cellular processes that take... (Review)
Review
The endoplasmic reticulum (ER) is a hotspot for many essential cellular functions. The ER membrane is highly dynamic, which affects many cellular processes that take place within the ER. One such process is ER-phagy, a selective degradation of ER fragments (including membranes and luminal content), which serves to preserve the size of ER while adapting its morphology under basal and stress conditions. In order to be degraded, the ER undergoes selective fragmentation facilitated by specialized ER-shaping proteins that also act as ER-phagy receptors. Their ability to sense and induce membrane curvature, as well as to bridge the ER with autophagy machinery, allows for a successful ER fragmentation and delivery of these fragments to the lysosome for degradation and recycling. In this review, we provide insights into ER-phagy from the perspective of membrane remodeling. We highlight the importance of ER membrane dynamics during ER-phagy and emphasize how its dysregulation reflects on human physiology and pathology.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Lysosomes; Membrane Proteins
PubMed: 35452617
DOI: 10.1016/j.molcel.2022.02.018 -
EMBO Reports Aug 2022Eukaryotic cells adequately control the mass and functions of organelles in various situations. Autophagy, an intracellular degradation system, largely contributes to... (Review)
Review
Eukaryotic cells adequately control the mass and functions of organelles in various situations. Autophagy, an intracellular degradation system, largely contributes to this organelle control by degrading the excess or defective portions of organelles. The endoplasmic reticulum (ER) is an organelle with distinct structural domains associated with specific functions. The ER dynamically changes its mass, components, and shape in response to metabolic, developmental, or proteotoxic cues to maintain or regulate its functions. Therefore, elaborate mechanisms are required for proper degradation of the ER. Here, we review our current knowledge on diverse mechanisms underlying selective autophagy of the ER, which enable efficient degradation of specific ER subdomains according to different demands of cells.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Macroautophagy
PubMed: 35758175
DOI: 10.15252/embr.202255192 -
BioMed Research International 2022Oxidative stress is an imbalance between free radicals and the antioxidant system causing overgeneration of free radicals (oxygen-containing molecules) ultimately... (Review)
Review
Oxidative stress is an imbalance between free radicals and the antioxidant system causing overgeneration of free radicals (oxygen-containing molecules) ultimately leading to oxidative damage in terms of lipid peroxidation, protein denaturation, and DNA mutation. Oxidative stress can activate autophagy to alleviate oxidative damage and maintain normal physiological activities of cells by degrading damaged organelles or local cytoplasm. When oxidative stress is not eliminated by autophagy, it activates the apoptosis cascade. This review provides a brief summary of mitochondrial-endoplasmic reticulum communication-mediated oxidative stress and autophagy. Mitochondria and endoplasmic reticulum being important organelles in cells are directly or indirectly connected to each other through mitochondria-associated endoplasmic reticulum membranes and jointly regulate oxidative stress and autophagy. The reactive oxygen species (ROS) produced by the mitochondrial respiratory chain are the main inducers of oxidative stress. Damaged mitochondria can be effectively cleared by the process of mitophagy mediated by PINK1/parkin pathway, Nix/BNIP3 pathways, and FUNDC1 pathway, avoiding excessive ROS production. However, the mechanism of mitochondrial-endoplasmic reticulum communication in the regulation of oxidative stress and autophagy is rarely known. For this reason, this review explores the mutual connection of mitochondria and endoplasmic reticulum in mediating oxidative stress and autophagy through ROS and Ca and aims to provide part of the theoretical basis for alleviating oxidative stress through autophagy mediated by mitochondrial-endoplasmic reticulum communication.
Topics: Antioxidants; Autophagy; Cell Communication; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Oxidative Stress; Oxygen; Protein Kinases; Reactive Oxygen Species; Ubiquitin-Protein Ligases
PubMed: 36164446
DOI: 10.1155/2022/6459585 -
International Journal of Molecular... Dec 2022Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments,... (Review)
Review
Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments, and the regulation of Ca homeostasis. Before leaving the organelle, proteins must be folded and post-translationally modified. Protein folding and revision require molecular chaperones and a favorable ER environment. When in stressful situations, ER luminal conditions or chaperone capacity are altered, and the cell activates signaling cascades to restore a favorable folding environment triggering the so-called unfolded protein response (UPR) that can lead to autophagy to preserve cell integrity. However, when the UPR is disrupted or insufficient, cell death occurs. This review examines the links between UPR signaling, cell-protective responses, and death following ER stress with a particular focus on those mechanisms that operate in neurons.
Topics: Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum; Signal Transduction; Cell Death; Molecular Chaperones
PubMed: 36499512
DOI: 10.3390/ijms232315186 -
Physiological Reviews Jul 2022ER-phagy (reticulophagy) defines the degradation of portions of the endoplasmic reticulum (ER) within lysosomes or vacuoles. It is part of the self-digestion (i.e.,... (Review)
Review
ER-phagy (reticulophagy) defines the degradation of portions of the endoplasmic reticulum (ER) within lysosomes or vacuoles. It is part of the self-digestion (i.e., autophagic) programs recycling cytoplasmic material and organelles, which rapidly mobilize metabolites in cells confronted with nutrient shortage. Moreover, selective clearance of ER subdomains participates in the control of ER size and activity during ER stress, the reestablishment of ER homeostasis after ER stress resolution, and the removal of ER parts in which aberrant and potentially cytotoxic material has been segregated. ER-phagy relies on the individual and/or concerted activation of the ER-phagy receptors, ER peripheral or integral membrane proteins that share the presence of LC3/Atg8-binding motifs in their cytosolic domains. ER-phagy involves the physical separation of portions of the ER from the bulk ER network and their delivery to the endolysosomal/vacuolar catabolic district. This last step is accomplished by a variety of mechanisms including macro-ER-phagy (in which ER fragments are sequestered by double-membrane autophagosomes that eventually fuse with lysosomes/vacuoles), micro-ER-phagy (in which ER fragments are directly engulfed by endosomes/lysosomes/vacuoles), or direct fusion of ER-derived vesicles with lysosomes/vacuoles. ER-phagy is dysfunctional in specific human diseases, and its regulators are subverted by pathogens, highlighting its crucial role for cell and organism life.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Lysosomes; Membrane Proteins
PubMed: 35188422
DOI: 10.1152/physrev.00038.2021 -
Ageing Research Reviews Jul 2023Organelles form tight connections through membrane contact sites, thereby cooperating to regulate homeostasis and cell function. Among them, the contact between... (Review)
Review
Organelles form tight connections through membrane contact sites, thereby cooperating to regulate homeostasis and cell function. Among them, the contact between endoplasmic reticulum (ER), the main intracellular calcium storage organelles, and mitochondria has been recognized for decades, and its main roles in the ion and lipid transport, ROS signaling, membrane dynamic changes and cellular metabolism are basically determined. At present, many tumor chemotherapeutic drugs rely on ER-mitochondrial calcium signal to function, but the mechanism of targeting resident molecules at the mitochondria-associated endoplasmic reticulum membranes (MAM) to sensitize traditional chemotherapy and the new tumor therapeutic targets identified based on the signal pathways on the MAM have not been thoroughly discussed. In this review, we highlight the key roles of various signaling pathways at the ER-mitochondria contact site in tumorigenesis and focus on novel anticancer therapy strategies targeting potential targets at this contact site.
Topics: Humans; Calcium; Mitochondria; Endoplasmic Reticulum; Signal Transduction; Neoplasms
PubMed: 37164161
DOI: 10.1016/j.arr.2023.101951 -
Trends in Cell Biology Apr 2023Calcium ion (Ca) is a ubiquitous and versatile signaling molecule controlling a wide variety of cellular processes, such as proliferation, cell death, migration, and... (Review)
Review
Calcium ion (Ca) is a ubiquitous and versatile signaling molecule controlling a wide variety of cellular processes, such as proliferation, cell death, migration, and immune response, all fundamental processes essential for the establishment of cancer. In recent decades, the loss of Ca homeostasis has been considered an important driving force in the initiation and progression of malignant diseases. The primary intracellular Ca store, the endoplasmic reticulum (ER), plays an essential role in maintaining Ca homeostasis by coordinating with other organelles and the plasma membrane. Here, we discuss the dysregulation of ER-centered Ca homeostasis in cancer, summarize Ca-based anticancer therapeutics, and highlight the significance of furthering our understanding of Ca homeostasis regulation in cancer.
Topics: Humans; Calcium; Endoplasmic Reticulum; Cell Death; Calcium Signaling; Neoplasms; Homeostasis
PubMed: 35915027
DOI: 10.1016/j.tcb.2022.07.004 -
Cells May 2022Calreticulin is an endoplasmic Ca binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein... (Review)
Review
Calreticulin is an endoplasmic Ca binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein supports Ca-dependent signaling events that are critical to cardiomyocyte differentiation and cardiogenesis. The increased expression of calreticulin and endoplasmic reticulum/sarcoplasmic reticulum Ca capacity produces cardiomyocytes with enhanced efficiency, and detrimental mechanical stretching of cardiac fibroblasts, leading to cardiac pathology. Deletion of the calreticulin gene in adult cardiomyocytes results in left ventricle dilation, an impaired electrocardiogram, and heart failure. These observations indicate that a well-adjusted endoplasmic reticulum and calreticulin-dependent Ca pool in cardiomyocytes are critical for the maintenance of proper cardiac function.
Topics: Calcium; Calreticulin; Endoplasmic Reticulum; Myocytes, Cardiac; Sarcoplasmic Reticulum
PubMed: 35681417
DOI: 10.3390/cells11111722 -
Seminars in Cancer Biology Nov 2020Cancer cells encounter numerous stresses that pose a threat to their survival. Tumor microenviroment stresses that perturb protein homeostasis can produce endoplasmic... (Review)
Review
Cancer cells encounter numerous stresses that pose a threat to their survival. Tumor microenviroment stresses that perturb protein homeostasis can produce endoplasmic reticulum (ER) stress, which can be counterbalanced by triggering the unfolded protein response (UPR) which is considered the canonical ER stress response. The UPR is characterized by three major proteins that lead to specific changes in transcriptional and translational programs in stressed cells. Activation of the UPR can induce apoptosis, but also can induce cytoprotective programs such as autophagy. There is increasing appreciation for the role that UPR-induced autophagy plays in supporting tumorigenesis and cancer therapy resistance. More recently several new pathways that connect cell stresses, components of the UPR and autophagy have been reported, which together can be viewed as non-canonical ER stress responses. Here we review recent findings on the molecular mechanisms by which canonical and non-canonical ER stress responses can activate cytoprotective autophagy and contribute to tumor growth and therapy resistance. Autophagy has been identified as a druggable pathway, however the components of autophagy (ATG genes) have proven difficult to drug. It may be the case that targeting the UPR or non-canonical ER stress programs can more effectively block cytoprotective autophagy to enhance cancer therapy. A deeper understanding of these pathways could provide new therapeutic targets in cancer.
Topics: Animals; Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Neoplasms; Signal Transduction; Unfolded Protein Response
PubMed: 31838023
DOI: 10.1016/j.semcancer.2019.11.007