Figure 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Stages of apoptosis. (A) The first morphological symptom of apoptosis is a change at the nucleus level. (B) Chromatin undergoes condensation and aggregates under the nuclear membrane, then the nucleus shrinks and undergoes fragmentation. (C) Next stage of "dying" is cytoplasm condensation and creation of characteristic bubbles on the cell surface. (D) Apoptotic bodies are constructed of cell fragments and consist of organelles, cytoplasm and chromatin. (E) The final stage of apoptosis is apoptotic bodies phagocytosis.
Source publication
Autophagy can play a double role in cancerogenesis: it can either inhibit further development of the disease or protect cells, causing stimulation of tumour growth. This phenomenon is called “autophagy paradox”, and is characterised by the features that the autophagy process provides the necessary substrates for biosynthesis to meet the cell’s ener...
Context in source publication
Context 1
... bodies created in this process contain cytoplasm with tightly packed cell organelles and with fragments of a nucleus. Subsequently, apoptotic bodies undergo phagocytosis, a process in which macrophages, parenchymal cells and histiocides take part (Fig- ure 1). The most important feature of apoptosis is the absence of an inflammatory reaction in the proximity of the dying cells, caused by the facts that: During apoptosis, cells do not disintegrate; There is no secondary necrosis, due to the immense pace of the phagocytosis; Phagocytes (such as macrophages, histiocytes, interstitial cells) do not release antiinflammatory cytokines [14]. ...
Citations
... As a highly conserved metabolic process, autophagy recycles substances to allow cells to adapt to poor environments by degrading damaged organelles and proteins in cells (He et al., 2018). Under normal physiologic conditions, autophagy is kept at low levels, but stress or nutrient deficiency can activate autophagy to maintain normal cell function (Chmurska et al., 2021). However, excessive autophagy exacerbates neuronal injury. ...
Objective:
Lidocaine has been reported to induce neurotoxicity, which is further enhanced by high glucose levels. This study is aimed to explore the underlying mechanisms of lidocaine neurotoxicity in spinal cord neurons of diabetes.
Methods:
Take thirty specific pathogen-free (SPF) healthy Sprague-Dawley (SD) rats and thirty Goto-Kakizaki (GK) rats, aged 12 weeks, weighing 180-200 g. The spinal cord neurons of rats were isolated and cultured in vitro. Cell Counting Kit-8 was used to detect cell proliferation to determine the appropriate concentration and duration of lidocaine. Mitochondrial function was assessed using ATP content, cellular oxygen consumption rate, mitochondrial membrane potential, ROS production, and mitochondrial ultrastructure. Western blot was applied to detect the expression of autophagy- and mitophagy-related molecules PINK1, p-AMPK, LC-3II/LC3-I ratio and mTORC1. Immunofluorescent staining was used to detect the expression of PINK1 and LC3.
Results:
Lidocaine decreased cell viability of spinal cord neurons in concentration- and time-dependent manners. And lidocaine treatment aggravated mitochondrial dysfunction in GK rats. Furthermore, mitophagy was activated in diabetes, and lidocaine exposure up-regulated mitophagy. AMPK activator MK8722 aggravated mitochondrial damage, increased the expression of PINK1, p-AMPK, LC-3II/LC3-I ratio, and decreased the expression of mTORC1, while AMPK inhibitor Compound C and autophagy inhibitor Bafilomycin A1 reduced mitochondrial damage and decreased the expression of PINK1, p-AMPK, LC-3II/LC3-I ratio, and increased the expression of mTORC1.
Conclusions:
Lidocaine induced neurotoxicity of spinal cord neurons in GK rats via AMPK-mediated mitophagy.
... In cancer-related processes, autophagy has two roles: on the one hand, it may suppress tumor progression through the elimination of oncogenic proteins and damaged organelles; on the other hand, autophagy often contributes to tumor progression and therapy resistance as an essential mechanism for tumor survival and growth under stress conditions [18]. Dankó et al. targeted metabolic rewiring, mammalian target of rapamycin (mTOR) hyperactivity, and mitochondrial functions through treating breast cancer cells using a rapamycin plus doxycycline combination. ...
... Although autophagy acts as a doubleedged sword during different stages of tumor progression, novel results derived from different tumor cell lines published in this issue [19,20] show that autophagy could be targeted in future cancer therapies as well. However, first, further investigations are needed to address important questions regarding autophagy and cancer therapy resistance, and the issue of autophagy and cancer stem cells; in addition, novel methods should be developed to track autophagy in patients [18]. ...
... Although autophagy acts as a doubleedged sword during different stages of tumor progression, novel results derived from different tumor cell lines published in this issue [19,20] show that autophagy could be targeted in future cancer therapies as well. However, first, further investigations are needed to address important questions regarding autophagy and cancer therapy resistance, and the issue of autophagy and cancer stem cells; in addition, novel methods should be developed to track autophagy in patients [18]. The core apoptotic pathway was identified in the worm [22]. ...
A careful balance between cell death and survival is of key importance when it comes to the maintenance of cellular homeostasis [...].
... Autophagy is an important feedback process of cells under pressure. Autophagy realizes self-digestion and catabolism by phagocytic organelles and degradation of cell contents, so as to maintain the homeostasis balance of cells (18,19). Autophagy plays an important role in maintaining vital activities and immune function and is closely related to tumors and other diseases. ...
Acute myeloid leukemia (AML) is a complex mixed entity composed of malignant tumor cells, immune cells and stromal cells, with intra-tumor and inter-tumor heterogeneity. Single-cell RNA sequencing enables a comprehensive study of the highly complex tumor microenvironment, which is conducive to exploring the evolutionary trajectory of tumor cells. Herein, we carried out comprehensive analyses of aggrephagy-related cell clusters based on single-cell sequencing for patients with acute myeloid leukemia. A total of 11 specific cell types (T, NK, CMP, Myeloid, GMP, MEP, Promono, Plasma, HSC, B, and Erythroid cells) using t-SNE dimension reduction analysis. Several aggrephagy-related genes were highly expressed in the 11 specific cell types. Using Monocle analysis and NMF clustering analysis, six aggrephagy-related CD8⁺ T clusters, six aggrephagy-related NK clusters, and six aggrephagy-related Mac clusters were identified. We also evaluated the ligand-receptor links and Cell–cell communication using CellChat package and CellChatDB database. Furthermore, the transcription factors (TFs) of aggrephagy-mediated cell clusters for AML were assessed through pySCENIC package. Prognostic analysis of the aggrephagy-related cell clusters based on R package revealed the differences in prognosis of aggrephagy-mediated cell clusters. Immunotherapy of the aggrephagy-related cell clusters was investigated using TIDE algorithm and public immunotherapy cohorts. Our study revealed the significance of aggrephagy-related patterns in tumor microenvironment, prognosis, and immunotherapy for AML.
... Autophagy promotes cell growth and survival by providing metabolic substrates for biosynthesis, thus, fulfilling the metabolic demands of proliferating cancer cells. Besides, autophagy is also responsible for inducing chemoresistance in cancer cells (120,121). There are also reports suggesting that although mTORC1inhibition prevents protein synthesis and cell proliferation, mTORC2 may activate the PI3K-Akt signaling pathway and promote tumor survival (106). ...
Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic sensor that is pivotal for the maintenance of cellular energy homeostasis. AMPK contributes to diverse metabolic and physiological effects besides its fundamental role in glucose and lipid metabolism. Aberrancy in AMPK signaling is one of the determining factors which lead to the development of chronic diseases such as obesity, inflammation, diabetes, and cancer. The activation of AMPK and its downstream signaling cascades orchestrate dynamic changes in the tumor cellular bioenergetics. It is well documented that AMPK possesses a suppressor role in the context of tumor development and progression by modulating the inflammatory and metabolic pathways. In addition, AMPK plays a central role in potentiating the phenotypic and functional reprogramming of various classes of immune cells which reside in the tumor microenvironment (TME). Furthermore, AMPK-mediated inflammatory responses facilitate the recruitment of certain types of immune cells to the TME, which impedes the development, progression, and metastasis of cancer. Thus, AMPK appears to play an important role in the regulation of anti-tumor immune response by regulating the metabolic plasticity of various immune cells. AMPK effectuates the metabolic modulation of anti-tumor immunity via nutrient regulation in the TME and by virtue of its molecular crosstalk with major immune checkpoints. Several studies including that from our lab emphasize on the role of AMPK in regulating the anticancer effects of several phytochemicals, which are potential anticancer drug candidates. The scope of this review encompasses the significance of the AMPK signaling in cancer metabolism and its influence on the key drivers of immune responses within the TME, with a special emphasis on the potential use of phytochemicals to target AMPK and combat cancer by modulating the tumor metabolism.
... Apoptosis and autophagy are the two main mechanisms leading to programmed cell death. Unlike apoptosis, the role of autophagy in cancer is complex [30,60]. Under certain stress conditions, upregulation of autophagy may lead to cell death. ...
Background
Aggressive B-cell non-Hodgkin’s lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed.
Methods
We investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo.
Results
CBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro.
Conclusions
CBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL.
... Autophagy plays an important and dual role in tumor suppression and promotion in different contexts. The controversial aspects of autophagy in cancer have been reviewed and reported [5][6][7]. Autophagy removes damaged components of the cells and transfers harmful products to lysosomal degradation to prevent further cellular damage [8]. Autophagy also induces autophagic or programmed cell death to suppress cancer development [9]. ...
... Defects in autophagy can cause cellular damage to make genetically unstable cells, and initiate cancer development. Paradoxically, autophagy fulfills the high energy and metabolic demands of cancer cells and allows them to develop tolerance against stress [5]. Autophagy enables cancer cells to survive stresses such as energy deprivation and hypoxia [6]. ...
Autophagy is a cellular process that removes damaged components of cells and recycles them as biochemical building blocks. Autophagy can also be induced to protect cells in response to intra- and extracellular stresses, including damage to cellular components, nutrient deprivation, hypoxia, and pathogenic invasion. Dysregulation of autophagy has been attributed to various diseases. In particular, autophagy protects cancer cells by supporting tumor cell survival and the development of drug resistance. Understanding the pathophysiological mechanisms of autophagy in cancer has stimulated the research on discovery and development of specific inhibitors targeting various stages of autophagy. In recent years, Unc-51-like autophagy-activating kinase (ULK) inhibitors have become an attractive strategy to treat cancer. This review summarizes recent discoveries and developments in small-molecule ULK inhibitors and their potential as anticancer agents. We focused on structural features, interactions with binding sites, and biological effects of these inhibitors. Overall, this review will provide guidance for using ULK inhibitors as chemical probes for autophagy in various cancers and developing improved ULK inhibitors that would enhance therapeutic benefits in the clinic.
... Autophagy is the most common type of NAPCD, and as a highly conserved physiological process, it removes damaged organelles and abnormal proteins through lysosomal degradation [40]. Autophagy is implicated in various pathological and physiological processes, including neurodegenerative diseases [41], the maintenance of intracellular homeostasis [42], inflammation [43], and cancer [44]. Autophagy is widely believed to have a dual effect on cells. ...
Thyroid disorders are among the most common endocrinological conditions. As the prevalence of thyroid diseases increases annually, the exploration of thyroid disease mechanisms and the development of treatments are also gradually improving. With the gradual advancement of therapies, non-apoptotic programmed cell death (NAPCD) has immense potential in inflammatory and neoplastic diseases. Autophagy, pyroptosis, ferroptosis, and immunogenic cell death are all classical NAPCD. In this paper, we have compiled the recent mechanistic investigations of thyroid diseases and established the considerable progress by NAPCD in thyroid diseases. Furthermore, we have elucidated the role of various types of NAPCD in different thyroid disorders. This will help us to better understand the pathophysiology of thyroid-related disorders and identify new targets and mechanisms of drug resistance, which may facilitate the development of novel diagnostic and therapeutic strategies for patients with thyroid diseases. Here, we have reviewed the advances in the role of NAPCD in the occurrence, progression, and prognosis of thyroid diseases, and highlighted future research prospects in this area.
... In terms of this review, we can view autophagy as a system for generating non-glucose carbon skeletons for metabolic energy production, and hence we can place autophagy near the metabolic functional heuristic core of PGRMC1's proposed ancestral eukaryogenic role (regulating energy production by mitochondria in response to oxygen levels). Autophagy plays a critical role in the metabolism and clinical phenotype of many tumors [135,136], and other pathologies such as Alzheimer's disease [137]. PGRMC1 regulates the induction autophagy by forming protein complexes with MAP1LC3 (microtubuleassociated protein 1 light chain 3, or LC3) and UVRAG (UV radiation resistance associated/UV radiation associated gene) [138]. ...
The title usage of Unde venisti ‘from where have you come’ is from a now dead language (Latin) that foundationally influenced modern English (not the major influence, but an essential formative one). This is an apt analogy for how both the ancient eukaryotic and eumetazoan functions of PGRMC proteins (PGRMC1 and PGRMC2 in mammals) probably influence modern human biology: via a formative trajectory from an evolutionarily foundational fulcrum. There is an arguable probability, although not a certainty, that PGRMC-like proteins were involved in eukaryogenesis. If so, then the proto-eukaryotic ancestral protein is modelled as having initiated the oxygen-induced and CYP450 (Cytochrome P450)-mediated synthesis of sterols in the endoplasmic reticulum to regulate proto-mitochondrial activity and heme homeostasis, as well as having enabled sterol transport between endoplasmic reticulum (ER) and mitochondria membranes involving the actin cytoskeleton, transport of heme from mitochondria, and possibly the regulation/origins of mitosis/meiosis. Later, during animal evolution, the last eumetazoan common ancestor (LEUMCA) acquired PGRMC phosphorylated tyrosines coincidentally with the gastrulation organizer, Netrin/deleted in colorectal carcinoma (DCC) signaling, muscle fibers, synapsed neurons, and neural recovery via a sleep-like process. Modern PGRMC proteins regulate multiple functions, including CYP450-mediated steroidogenesis, membrane trafficking, heme homeostasis, glycolysis/Warburg effect, fatty acid metabolism, mitochondrial regulation, and genomic CpG epigenetic regulation of gene expression. The latter imposes the system of differentiation status-sensitive cell-type specific proteomic complements in multi-tissued descendants of the LEUMCA. This paper attempts to trace PGRMC functions through time, proposing that key functions were involved in early eukaryotes, and were later added upon in the LEUMCA. An accompanying paper considers the implications of this awareness for human health and disease.
... Autophagy has a dual role in the development of cancer. It can not only promote the growth of tumor cells but also prevent the further development of the disease, the so-called "autophagy paradox" [78]. The complex relationship between autophagy and microorganisms can protect the body by activating the immune system. ...
Epstein–Barr virus (EBV) is a recognized oncogenic virus that is related to the occurrence of lymphoma, nasopharyngeal carcinoma (NPC), and approximately 10% of gastric cancer (GC). EBV is a herpesvirus, and like other herpesviruses, EBV has a biphasic infection mode made up of latent and lytic infections. It has been established that latent infection promotes tumorigenesis in previous research, but in recent years, there has been new evidence that suggests that the lytic infection mode could also promote tumorigenesis. In this review, we mainly discuss the contribution of the EBV lytic phase to tumorigenesis, and graphically illustrate their relationship in detail. In addition, we described the relationship between the lytic cycle of EBV and autophagy. Finally, we also preliminarily explored the influence of the tumorigenesis effect of the EBV lytic phase on the future treatment of EBV-associated tumors.
... However, there was little agreement on the role of autophagy in cancer. 183 There are indications that cancer cells present a strong adaptation to various conditions, like hypoxia and nutritional deprivation. As OMA1 is in the activation state to induce cellular autophagy and clear damaged cancer cells. ...
Mitochondria, the main provider of energy in eukaryotic cells, contains more than 1000 different proteins and is closely related to the development of cells. However, damaged proteins impair mitochondrial function, further contributing to several human diseases. Evidence shows mitochondrial proteases are critically important for protein maintenance. Most importantly, quality control enzymes exert a crucial role in the modulation of mitochondrial functions by degrading misfolded, aged, or superfluous proteins. Interestingly, cancer cells thrive under stress conditions that damage proteins, so targeting mitochondrial quality control proteases serves as a novel regulator for cancer cells. Not only that, mitochondrial quality control proteases have been shown to affect mitochondrial dynamics by regulating the morphology of optic atrophy 1 (OPA1), which is closely related to the occurrence and progression of cancer. In this review, we introduce mitochondrial quality control proteases as promising targets and related modulators in cancer therapy with a focus on caseinolytic protease P (ClpP), Lon protease (LonP1), high‐temperature requirement protein A2 (HrtA2), and OMA‐1. Further, we summarize our current knowledge of the advances in clinical trials for modulators of mitochondrial quality control proteases. Overall, the content proposed above serves to suggest directions for the development of novel antitumor drugs.
