Process of autophagy. Autophagy includes five phases: initiation, elongation and autophagosome formation, fusion, and autolysosome formation. Macromolecules are targeted to double-membrane vesicles called autophagosomes and then autolysosomes form by fusion with lysosomes. Autophagy is initiated by the ULK1 complex containing ULK, Atg13, FIP200, and Atg101. Autophagosome elongation and maturation involves two ubiquitin-like conjugation systems, such as the microtubule-associated protein 1 light chain 3 (LC3) and the Atg12 systems. The autophagosome fuses with a lysosome to form an autolysosome, which degrades macromolecules into amino acids, fatty acids, and nucleotides.

Process of autophagy. Autophagy includes five phases: initiation, elongation and autophagosome formation, fusion, and autolysosome formation. Macromolecules are targeted to double-membrane vesicles called autophagosomes and then autolysosomes form by fusion with lysosomes. Autophagy is initiated by the ULK1 complex containing ULK, Atg13, FIP200, and Atg101. Autophagosome elongation and maturation involves two ubiquitin-like conjugation systems, such as the microtubule-associated protein 1 light chain 3 (LC3) and the Atg12 systems. The autophagosome fuses with a lysosome to form an autolysosome, which degrades macromolecules into amino acids, fatty acids, and nucleotides.

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Development of a tumor is a very complex process, and invasion and metastasis of malignant tumors are hallmarks and are difficult problems to overcome. The tumor microenvironment plays an important role in controlling tumor fate and autophagy induced by the tumor microenvironment is attracting more and more attention. Autophagy can be induced by se...

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... P62/SQSTM1 is an autophagy receptor that links ubiquitinated proteins to LC3 promoting their degradation. Interestingly, p62/ SQSTM1 is itself degraded in the final steps of autophagic process (17). ...
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Adrenal masses are one of the most common tumors in humans. The majority are benign and non-functioning and therefore do not require immediate treatment. In contrast, the rare adrenal malignant tumors are often highly aggressive and with poor prognosis. Besides usually being detected in advanced stages, often already with metastases, one of the reasons of the unfavorable outcome of the patients with adrenal cancer is the absence of effective treatments. Autophagy is one of the intracellular pathways targeted by several classes of chemotherapeutics. Mitotane, the most commonly used drug for the treatment of adrenocortical carcinoma, was recently shown to also modulate autophagy. Autophagy is a continuous programmed cellular process which culminates with the degradation of cellular organelles and proteins. However, being a dynamic mechanism, understanding the autophagic flux can be highly complex. The role of autophagy in cancer has been described paradoxically: initially described as a tumor pro-survival mechanism, different studies have been showing that it may result in other outcomes, namely in tumor cell death. In adrenal tumors, this dual role of autophagy has also been addressed in recent years. Studies reported both induction and inhibition of autophagy as a treatment strategy of adrenal malignancies. Importantly, most of these studies were performed using cell lines. Consequently clinical studies are still required. In this review, we describe what is known about the role of autophagy modulation in treatment of adrenal tumors. We will also highlight the aspects that need further evaluation to understand the paradoxical role of autophagy in adrenal tumors.
... Cells can obtain energy during the autophagic process under various cellular stresses, including nutrient-depleted, ischemia, and oxidative stress (18,19). In tumor cells, autophagy may act as a self-defensive mechanism that contributes to tumor cell survival by removing toxins and garbage (20,21). Abnormal autophagic activity also may cause the inappropriate degradation of cell components that are indispensable for tumor c2ell survival, resulting in autophagic cell death (22). ...
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Background: Existing research shows that long non-coding RNAs (lncRNAs) have important regulatory effects in gastric cancer (GC). In recent years, focally amplified lncRNA on chromosome 1 (FALEC) has been repeatedly reported to have carcinogenic effects in thyroid carcinoma, colorectal cancer, and endometrial cancer, etc. While the role and mechanism of FALEC during GC tumorigenesis remains unclear. Methods: The levels of FALEC, microRNA-203b (miR-203b), and Recombinant Pim-3 Oncogene (PIM3) were confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell autophagy, proliferation, apoptosis, migration, and invasion were estimated using western blot, transmission electron microscopy (TEM), cell counting kit-8 (CCK-8), flow cytometer, and Transwell assays. The interaction between miR-203b and FALEC or PIM3 was verified using a dual-luciferase reporter assay. Moreover, the involvement of miR-203b and PIM3 in the regulatory effects of FALEC on GC was determined with rescue experiments. Results: The results showed that FALEC and PIM3 were highly expressed, while miR-203b was lowly expressed, in GC. FALEC knockdown repressed GC cell proliferation, migration, and invasion, and promoted apoptosis and autophagy in vitro. Meanwhile, FALEC knockdown prevented growth and induced GC autophagy in vivo. This shows that FALEC upregulated PIM3 by sponging miR-203b in GC cells. Besides, FALEC induced the malignant behaviors of GC cells by regulating the miR-203b/PIM3 axis. Conclusions: The FALEC/miR-203b/PIM3 axis might be a promising therapeutic target for therapy in GC patients.
... Tumor microenvironment is a new concept in tumor research, and it is also an important symbol of tumor research. Tumor microenvironment provides nutrients to cancer cells to ensure their survival, and also provides positive conditions for the invasion and metastasis of cancer cells (21). In recent years, the overall level of medical treatment has been improving, and many new methods have emerged for the treatment of PC. ...
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Background: Pancreatic cancer (PC) is one of the most common malignant tumors of the digestive tract. Its clinical symptoms are obscure and atypical. It is difficult to diagnose and treat. Tumor cells mainly obtain energy through glycolysis to promote their growth. Inhibiting glycolysis can inhibit proliferation and kill tumor cells. Methods: Using bioinformatics method, we investigate the relationships between glycolysis-related genes and PC tumor samples' epidemiologic information comprehensively. Results: Different expression levels of 27 genes were identified. Using bioinformatics methods, we plotted two subgroup curves based on glycolysis-related gene expression level. Potential predictive genes were screened and their prognostic values were analyzed. Survival among high-risk group and low risk group had significant difference. Receiver operating characteristic (ROC) curve analysis indicated that area under curve (AUC) of 10 genes was greater than 0.8. These genes could be used for clinical diagnosis and prediction for PC. Two potential predictors [Kinesin Family Member 20A (KIF20A) and MET Proto-Oncogene, Receptor Tyrosine Kinase (MET)] that met the independent predictive value were selected. In univariate analysis, we screened out 3 regulators MET, protein kinase CAMP-activated catalytic subunit alpha (PRKACA) and KIF20A. According to the 3 regulatory factors, the prognostic signals of PC were constructed, by which the samples with good prognosis and poor prognosis can be clearly distinguished independently of potential confounding factors. Conclusions: Our results indicate that for PC, glycolysis -related genes could be promising therapeutic targets or prognostic indicators.
... In normal cells, autophagy clears ROS, damaged organelles and reduces DNA damage [19], thus preventing the transformation into tumor cells [20]. On the other hand, tumor cells use autophagic pathways to overcome nutrient starvation and to facilitate tumor growth, to be precise, pancreatic and lung cancers are highly reliant on autophagy activation to meet growth demands [21,22]. Apart from inhibition of apoptosis, tumor cells use metabolite turnover and absorption to meet the increased metabolic demand during their growth. ...
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Autophagy is the process of recycling and utilization of degraded organelles and macromolecules in the cell compartments formed during the fusion of autophagosomes with lysosomes. During autophagy induction the healthy and tumor cells adapt themselves to harsh conditions such as cellular stress or insufficient supply of nutrients in the cell environment to maintain their homeostasis. Autophagy is currently seen as a form of programmed cell death along with apoptosis and necroptosis. In recent years multiple studies have considered the autophagy as a potential mechanism of anticancer therapy in malignant glioma. Although, subsequent steps in autophagy development are known and well-described, on molecular level the mechanism of autophagosome initiation and maturation using autophagy-related proteins is under investigation. This article reviews current state about the mechanism of autophagy, its molecular pathways and the most recent studies on roles of autophagy-related proteins and their isoforms in glioma progression and its treatment.
... Cells can obtain energy during the autophagic process under various cellular stresses, including nutrient depletion, ischemia, and oxidative stress [36]. In tumor cells, autophagy may act as a self-defensive mechanism which contributes to tumor cell survival by removing toxins and garbage [37], while abnormal autophagic activity may cause the inappropriate degradation of cell components that are indispensable for tumor cell survival, resulting in autophagic cell death [38]. Currently, circRNAs have been certified to have a key regulatory effect on tumor cell autophagy [39,40]. ...
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Background: Increased levels of circRNAs have been identified in a variety of cancers. However, the specific functions and mechanisms of circRNAs in neuroblastoma (NB) have not been fully explored. Methods: The levels of hsa_circ_0045997, hsa_circ_0080307, hsa_circ_0013401, hsa_circ_0077578, and microRNA-195 were confirmed by RT-qPCR in NB. Gain- and loss-of-function assays and rescue experiments were conducted to determine the influence of hsa_circ_0013401, miR-195, and P21-activated kinase 2 (PAK2) on the proliferation, apoptosis, autophagy, migration, and invasion of NB cells. Regulatory gene targets were validated by the luciferase assay. A xenograft mouse model was used to determine the in vivo effects of hsa_circ_0013401. Results: hsa_circ_0013401 was highly expressed, miR-195 was lowly expressed, and there was a negative correlation between hsa_circ_0013401 and miR-195 in NB. The inhibitory effects of hsa_circ_0013401 knockdown suppressed the proliferation, migration, and invasion and induced the apoptosis and autophagy of NB cells by targeting miR-195 to downregulate PAK2 expression. Luciferase reporter assays showed that miR-195 was a direct target of hsa_circ_0013401, and PAK2 was the downstream target gene of miR-195. In vivo studies showed that hsa_circ_0013401 promotes tumor formation. Conclusions: hsa_circ_0013401 induced NB progression through miR-195 to enhance PAK2. Therefore, we might highlight a novel regulatory axis (hsa_circ_0013401/miR-195/PAK2) in NB.
... Cells can obtain energy during the autophagic process under various cellular stresses, including nutrient-depleted, ischemia, oxidative stress [15,16]. In tumor cells, autophagy may act as a self-defensive mechanism that contributes to tumor cell survival by removing toxins and garbage [17,18]. However, abnormal autophagic activity may cause the inappropriate degradation of cell components that are indispensable for tumor cell survival, resulting in autophagic cell death [19]. ...
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Background Pieces of evidences have shown the important regulatory effects of long non-coding RNAs (lncRNAs) in gastric cancer (GC). While it is not entirely clear for the role and mechanism of focally amplified lncRNA on chromosome 1 (FALEC) during GC tumorigenesis. Methods The levels of FALEC, microRNA-203b (miR-203b), and PIM3 were confirmed by qRT-PCR. And cell autophagy, proliferation, apoptosis, migration, and invasion were estimated using western blot for autophagy-related proteins, Transmission electron microscopy (TEM), CCK-8, flow cytometer, and Transwell assays in NCI-N87 cells and Xenograft tumor. Besides, the interaction between miR-203b and FALEC or PIM3 was verified using a dual-luciferase reporter assay. Moreover, the involvement of miR-203b and PIM3 in the regulatory effects of FALEC on GC was determined by rescue experiments. ResultsThe results proved that FALEC and PIM3 were highly expressed, while miR-203b was lowly expressed in GC. FALEC knockdown repressed GC cell proliferation, migration, and invasion, promoted apoptosis and autophagy in vitro . Meanwhile, FALEC knockdown prevented growth and induced GC autophagy in vivo . In mechanism, FALEC could upregulate PIM3 by sponging miR-203b in GC cells. Besides, FALEC induced the malignant behaviors of GC cells by regulating the miR-203b/PIM3 axis. ConclusionsTherefore, FALEC/miR-203b/PIM3 axis might act as the promising therapeutic target for the therapy of GC patients.
... [18,19] Indeed, autophagy can repair and reverse cell damage caused by heating, resulting in incomplete cell necrosis. [20][21][22] In order to overcome this treatment resistance, severer conditions (e.g., high temperature and extended irradiation time) are applied in PTT, which may cause accidental damage to nearby non-cancerous tissues. [23,24] Therefore, developing an advanced PTT platform that can effectively inhibit autophagy is very attractive, and could help achieve more targeted and speci c inhibition of tumors. ...
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Photothermal therapy (PTT) usually causes hyperthermia and damages healthy tissues. Developing a PTT platform using mild irradiation, while enhance the theraputical effects attracts increasing attention. Here, this study developed a theranostic poly(D,L-lactic-co-glycolic acid) (PLGA) nanoplatform loaded with a near-infrared (NIR) dye (new indocyanine Green IR820), autophagy inhibitor (chloroquine, CQ) and a fluorescence imaging agent (ZnCdSe/ZnS quantum dot, QD) by the double emulsion solvent evaporation technique (W1/O/W2). The resulting hybrid PLGA nanoparticles with IR820/ZnCdSe/ZnS/CQ co-loading (termed PIFC NPs) approximated 240 nm in diameter and had excellent monodispersity, fluorescence and size stability, and biocompatibility. PIFC NPs displayed photothermal effects, and the released CQ remarkably decreased autolysosome degeneration by lysosomes in cancer cells, thereby enhancing the suppressive effect on autophagy as well as resistance to photothermia. Anticancer effects were enhanced both in cellular and animal experiments attributed to the combined effects exerted by PIFC NPs and mild NIR irradiation. Moreover, PIFC NPs significantly accumulated in tumors because of enhanced permeability and retention (EPR) effect, enabling high-spatial resolution, real-time fluorescence imaging of solid tumors. The present study developed a novel PTT platform showing potentially enhanced therapeutic efficacy.
... Previous studies suggested that there was a complicated relationship between the pH and autophagy in different types of cells [28,29]. Gu and Wu et al. proved acidic microenvironment could inhibit autophagy activity via the PTEN/AKT pathway [30,31]. ...
... Herein, we have reported a pH-modulation strategy based on LDOs coated titanium implants to induce autophagy in MSCs and regulate their osteoblastic differentiation. Specifically, we have carried out western blot and immunofluorescence analysis ( Figure 5 and Figure S6) to investigate the autophagycharacteristic LC3 proteins in MSCs grown on different implant surface including Ti, AT, AT-Mg, AT-4Mg/Ga, AT-2Mg/Ga and AT-Mg/Ga at molecular levels, and the corresponding results evidently confirmed that the coating surface could show 28 elevated pH to enhance the autophagy in MSCs. Moreover, the basicity-enhanced autophagy could be inhibited after the addition of chloroquine (Figure 6), which is a well-established autophagy inhibitor. ...
Article
Osteoporotic fracture is generally hard to be fixed due to its abnormal microenvironment and cells metabolism, leading to poor osteointegration between the implants and surrounding bone tissue. Under osteoporotic condition, the microenvironmental pH would affect osteoblastic metabolism and bone formation/ resorption behavior. Thus, it is reasonable to regulate cell metabolism with implanted biomaterials to adjust the pH at osteoporotic fractures and improve the osteogenic ability. To confirm this hypothesis, we fabricated a series of Mg-Ga layered double oxide (LDO) nanosheets on the surfaces of alkali-heat-treated titanium (AT) implants (denoted as AT-xMg/yGa). We found that AT-Mg/Ga with equal molar ratio of Mg 2+ and Ga 3+ displayed good stability and formed a suitable alkaline microenvironment (about pH 8.5) over long term. Meanwhile, AT-Mg/Ga layers markedly promoted the autophagic activity and induced osteogenesis differentiation of mesenchymal stem cells (MSCs) while suppressing osteoclast generation. Furthermore, in vivo tests further verified that the AT-Mg/Ga implants suppressed osteoclastic bone resorption and prominently promoted new bone formation. Therefore, the fabricated AT-Mg/Ga implants have potential application in the rescue of osteoporosis by suppressing osteoclastogenesis and enhancing the osteogenesis.
... Currently, autophagy plays essential roles in different cellular processes and has been implicated to be involved in the pathogenesis of a wide variety of diseases, including cardiovascular diseases, 34,35 atherosclerosis, 36 neurodegenerative disorders 37 and more cancers. 7,38,39 Although several studies have indeed provided data to describe the anti-tumour effects of blue LED on cancers, its role and in-depth mechanisms remain unclear. Thus, our study firstly demonstrated the induction of autophagy by blue LED irradiation, leading to suppression of cell proliferation, migration and invasion in human OS. ...
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Osteosarcoma (OS) is the most common primary malignant bone tumour in adolescence. Lately, light-emitting diodes (LED)-based therapy has emerged as a new promising approach for several diseases. However, it remains unknown in human OS. Here, we found that the blue LED irradiation significantly suppressed the proliferation, migration and invasion of human OS cells, while we observed blue LED irradiation increased ROS production through increased NADPH oxidase enzymes NOX2 and NOX4, as well as decreased Catalase (CAT) expression levels. Furthermore, we revealed blue LED irradiation-induced autophagy characterized by alterations in autophagy protein markers including Beclin-1, LC3-II/LC3-I and P62. Moreover, we demonstrated an enhanced autophagic flux. The blockage of autophagy displayed a remarkable attenuation of anti-tumour activities of blue LED irradiation. Next, ROS scavenger N-acetyl-L-cysteine (NAC) and NOX inhibitor diphenyleneiodonium (DPI) blocked suppression of OS cell growth, indicating that ROS accumulation might play an essential role in blue LED-induced autophagic OS cell death. Additionally, we observed blue LED irradiation decreased EGFR activation (phosphorylation), which in turn led to Beclin-1 release and subsequent autophagy activation in OS cells. Analysis of EGFR colocalization with Beclin-1 and EGFR-immunoprecipitation (IP) assay further revealed the decreased interaction of EGFR and Beclin-1 upon blue LED irradiation in OS cells. In addition, Beclin-1 down-regulation abolished the effects of blue LED irradiation on OS cells. Collectively, we concluded that blue LED irradiation exhibited anti-tumour effects on OS by triggering ROS and EGFR/Beclin-1-mediated autophagy signalling pathway, representing a potential approach for human OS treatment.
... 21 Autophagy includes five phases: initiation, elongation, autophagosome formation, fusion, and autolysosome formation. 22 During autophagy, the cytosolic form of LC3 (LC3-I) is conjugated to phosphatidylethanolamine to form the LC3phosphatidylethanolamine conjugate (LC3-II), which is recruited to autophagosomal membranes. 23 Thus, measuring LC3 conversion (LC3-I to LC3-II) by immunoblotting has become a reliable method for monitoring autophagy and autophagy-related processes. ...
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Background: The pathogenesis of fibrous epulis is still quite unclear. Our recent genome-wide RNA sequencing analysis revealed that in fibrous epulis, RAS-PI3K-AKT-NF-κB pathway regulates the expression of Bcl-2 family and IAP family genes, leading to increased proliferation and the inhibition of apoptosis. The PI3K/AKT signaling pathway can promote autophagy in human gingival fibroblasts; therefore, the purpose of the present study was to identify whether autophagy is involved in the pathogenesis of fibrous epulis. Methods: Differentially expressed genes (DEGs) between fibrous epulis lesions and normal gingival tissues were identified using the PCR array. The expression levels of eighteen autophagy-related (ATG) family genes, twelve B-cell lymphoma 2 (Bcl-2) family genes, and eleven cysteine-dependent aspartate-directed protease (caspase) family genes were validated using quantitative real-time PCR (qRT-PCR). Autophagy induction was determined by measuring microtubule-associated protein light chain 3 (LC3) conversion (LC3-I to LC3-II) by immunoblot analysis. Results: The PCR array identified six upregulated genes, whereas no genes were expressed at significantly lower levels. The upregulated genes were BCL2, BCL2L1, CXCR4, HSP90AA1, HSPA8, and IGF1, which all belong to the "regulation of autophagy" group but not the "autophagy machinery components" group. qRT-PCR verified that the expression levels of BCL2, BCL2L1 (also known as BCL-XL), and BCL2L2 (also known as BCL-W) were significantly increased in fibrous epulis. No LC3-I to LC3-II conversion was observed. Conclusions: The present study reveals that in fibrous epulis, Bcl-2 and Bcl-xL coordinately mediate gingival cell escape from apoptosis, leading to uncontrolled proliferation. Moreover, ATG family genes are not activated, and autophagy is not involved in this process.