Impact Of Autophagy Research Articles

Autophagy flux in bladder cancer: Cell death crosstalk, drug and nanotherapeutics

Autophagy, a self-digestion mechanism, has emerged as a promising target in the realm of cancer therapy, particularly in bladder cancer (BCa), a urological malignancy characterized by dysregulated biological processes contributing to its progression. This highly conserved catabolic mechanism exhibits aberrant activation in pathological events, prominently featured in human cancers. The nuanced role of autophagy in cancer has been unveiled as a double-edged sword, capable of functioning as both a pro-survival and pro-death mechanism in a context-dependent manner. In BCa, dysregulation of autophagy intertwines with cell death mechanisms, wherein pro-survival autophagy impedes apoptosis and ferroptosis, while pro-death autophagy diminishes tumor cell survival. The impact of autophagy on BCa progression is multifaceted, influencing metastasis rates and engaging with the epithelial-mesenchymal transition (EMT) mechanism. Pharmacological modulation of autophagy emerges as a viable strategy to impede BCa progression and augment cell death. Notably, the introduction of nanoparticles for targeted autophagy regulation holds promise as an innovative approach in BCa suppression. This review underscores the intricate interplay of autophagy with cell death pathways and its therapeutic implications in the nuanced landscape of bladder cancer.

Sirtuins Affect Cancer Stem Cells via Epigenetic Regulation of Autophagy.

Sirtuins (SIRTs) are stress-responsive proteins that regulate several post-translational modifications, partly by acetylation, deacetylation, and affecting DNA methylation. As a result, they significantly regulate several cellular processes. In essence, they prolong lifespan and control the occurrence of spontaneous tumor growth. Members of the SIRT family have the ability to govern embryonic, hematopoietic, and other adult stem cells in certain tissues and cell types in distinct ways. Likewise, they can have both pro-tumor and anti-tumor effects on cancer stem cells, contingent upon the specific tissue from which they originate. The impact of autophagy on cancer stem cells, which varies depending on the specific circumstances, is a very intricate phenomenon that has significant significance for clinical and therapeutic purposes. SIRTs exert an impact on the autophagy process, whereas autophagy reciprocally affects the activity of certain SIRTs. The mechanism behind this connection in cancer stem cells remains poorly understood. This review presents the latest findings that position SIRTs at the point where cancer cells and autophagy interact. Our objective is to highlight the various roles of distinct SIRTs in cancer stem cell-related functions through autophagy. This would demonstrate their significance in the genesis and recurrence of cancer and offer a more precise understanding of their treatment possibilities in relation to autophagy.

Active Autophagy Is Associated with Favorable Outcome in Patients with Surgically Resected Cholangiocarcinoma.

Data on the impact of autophagy in primary cholangiocarcinoma (CCA) remain scarce. Here, we therefore investigated the role of active autophagy and its impact on survival in CCA patients. All CCA patients who underwent surgical resection with curative intent between 08/2005 and 12/2021 at University Hospital Frankfurt were evaluated. Autophagic key proteins were studied by immunohistochemistry. iCCA processed for gene expression profiling of immune-exhaustion gene sets was used for an autophagy approach in silico. Active autophagy was present in 23.3% of the 172 CCA patients. Kaplan-Meier curves revealed median OS of 68.4 months (95% CI = 46.9-89.9 months) and 32.7 months (95% CI = 23.6-41.8 months) for active and non-active autophagy, respectively (p ≤ 0.001). In multivariate analysis, absence of active autophagy (HR = 2, 95% CI = 1.1-3.5, p = 0.015) was an independent risk factor for OS. Differential-expression profiling revealed significantly upregulated histone deacetylases (HDAC) mRNA in patients showing non-active autophagy. In line with this, pan-acetylated lysine was significantly more prominent in CCA patients with ongoing autophagy (p = 0.005). Our findings strengthen the role of active autophagy as a prognostically relevant marker and a potential therapeutic target.

Unlocking the potential of Mesenchymal stem cells in liver Fibrosis: Insights into the impact of autophagy and aging.

Liver fibrosis is a chronic liver disease characterized by extracellular matrix protein accumulation, potentially leading to cirrhosis or hepatocellular carcinoma. Liver cell damage, inflammatory responses, and apoptosis due to various reasons induce liver fibrosis. Although several treatments, such as antiviral drugs and immunosuppressive therapies, are available for liver fibrosis, they only provide limited efficacy. Mesenchymal stem cells (MSCs) have become a promising therapeutic option for liver fibrosis, because they can modulate the immune response, promote liver regeneration, and inhibit the activation of hepatic stellate cells that contribute to disease development. Recent studies have suggested that the mechanisms through which MSCs gain their antifibrotic properties involve autophagy and senescence. Autophagy, a vital cellular self-degradation process, is critical for maintaining homeostasis and protecting against nutritional, metabolic, and infection-mediated stress. The therapeutic effects of MSCs depend on appropriate autophagy levels, which can improve the fibrotic process. Nonetheless, aging-related autophagic damage is associated with a decline in MSC number and function, which play a crucial role in liver fibrosis development. This review summarizes the recent advancements in the understanding of autophagy and senescence in MSC-based liver fibrosis treatment, presenting the key findings from relevant studies.

Orf virus induces complete autophagy to promote viral replication via inhibition of AKT/mTOR and activation of the ERK1/2/mTOR signalling pathway in OFTu cells

Orf virus (ORFV) is the causative agent of contagious ecthyma, which is an important zoonotic pathogen with a widespread distribution affecting sheep, goats and humans. Our previous research showed that autophagy can be induced in host cells by ORFV infection. However, the exact mechanism of ORFV-induced autophagy remains unknown. In this study, we investigated the underlying mechanisms of autophagy induced by ORFV in OFTu cells and the impact of autophagy on ORFV replication. By using specific autophagy inhibitors and activators, Western blotting, immunofluorescence and transmission electron microscopy imaging, we confirmed that ORFV infection triggered intracellular autophagosome accumulation and the activation of autophagic flux. Moreover, ORFV-induced autophagic activity was found to rely on an increase in the phosphorylation of tuberous sclerosis complex 2 (TSC2) and a decrease in the phosphorylation of mammalian target of rapamycin (mTOR), which is mediated by the suppression of the PI3K/AKT/mTOR signalling pathway and activation of the ERK1/2/mTOR signalling pathway. Furthermore, we investigated the role of mTOR-mediated autophagy during ORFV replication using pharmacological agents and demonstrated that ORFV-induced autophagy correlated positively with viral replication. Taken together, our data reveal the pathways of ORFV-induced autophagy and the impact of autophagy on ORFV replication, providing new insights into ORFV pathogenesis.

Impact of Autophagy on Prognosis of Patients With Dilated Cardiomyopathy

BackgroundAutophagy is a cellular process that degrades a cell’s own cytoplasmic components for energy provision and to maintain a proper intracellular environment. Left ventricular reverse remodeling (LVRR) promises a better prognosis for patients with dilated cardiomyopathy (DCM). ObjectivesThe authors tested the hypothesis that autophagy is involved in LVRR and has prognostic value in the human failing heart. MethodsUsing left ventricular endomyocardial biopsy specimens from 42 patients with DCM (21 LVRR-positive and 21 LVRR-negative) and 7 patients with normal cardiac function (control), the authors performed immunohistochemistry and immunofluorescent labeling of LC3 and cathepsin D and electron microscopic observation in addition to general morphometry under light microscopy. ResultsThe clinical characteristics of LVRR-positive patients were similar to those of the LVRR-negative patients, except for pulmonary artery pressure and left atrial dimension. Morphometry under light microscopy did not differ among specimens from DCM patients, regardless of their LVRR status. Electron microscopy revealed that autophagic vacuoles (autophagosomes and autolysosomes) and lysosomes were abundant within cardiomyocytes from DCM patients. Moreover, cardiomyocytes from LVRR-positive patients contained significantly more autophagic vacuoles with higher autolysosome ratios and cathepsin D expression levels than cardiomyocytes from LVRR-negative patients. Logistic regression analysis adjusted for age showed that increases in autophagic vacuole number and cathepsin D expression were predictive of LVRR. DCM patients who achieved LVRR experienced fewer cardiovascular events during the follow-up period. ConclusionsThe authors show that autophagy is a useful marker predictive of LVRR in DCM patients. This provides novel pathologic insight into a strategy for treating the failing DCM heart.

The Impact of Autophagy on The Differentiation of Immune Cells

Autophagy, as a conservative lysosomal degradation pathway, has been well studied for its multiple functions in the immune system. Autophagy has been gradually explored for the regulation of immune cell differentiation. In order to explore the specific mechanism, it is necessary to summarize the role of autophagy in the proliferation and differentiation of immune cells. It is summarized the effects of autophagy in some researches on the function and differentiation of immune cells by introducing the function of autophagy selective degradation. In this review, we discuss the effect of autophagy in the differentiation of immune cells.

The Role of Autophagy in Varicella Zoster Virus Infection.

Autophagy is an evolutionary conserved cellular process serving to degrade cytosolic organelles or foreign material to maintain cellular homeostasis. Autophagy has also emerged as an important process involved in complex interactions with viral pathogens during infection. It has become apparent that autophagy may have either proviral or antiviral roles, depending on the cellular context and the specific virus. While evidence supports an antiviral role of autophagy during certain herpesvirus infections, numerous examples illustrate how herpesviruses may also evade autophagy pathways or even utilize this process to their own advantage. Here, we review the literature on varicella zoster virus (VZV) and autophagy and describe the mechanisms by which VZV may stimulate autophagy pathways and utilize these to promote cell survival or to support viral egress from cells. We also discuss recent evidence supporting an overall antiviral role of autophagy, particularly in relation to viral infection in neurons. Collectively, these studies suggest complex and sometimes opposing effects of autophagy in the context of VZV infection. Much remains to be understood concerning these virus–host interactions and the impact of autophagy on infections caused by VZV.

Targeting the Autophagy Specific Lipid Kinase VPS34 for Cancer Treatment: An Integrative Repurposing Strategy.

The impact of autophagy on cancer treatment and its corresponding responsiveness has galvanized the scientific community to develop novel inhibitors for cancer treatment. Importantly, the discovery of inhibitors that targets the early phase of autophagy was identified as a beneficial choice. Despite the number of research in recent years, screening of the DrugBank repository (9591 molecules) for the Vacuolar protein sorting 34 (VPS34) has not been reported earlier. Therefore, the present study was designed to identify potential VPS34 antagonists using integrated pharmacophore strategies. Primarily, an energy-based pharmacophore and receptor cavity-based analysis yielded five (DHRRR) and seven featured (AADDHRR) pharmacophore hypotheses respectively, which were utilized for the database screening process. The glide score, the binding free energy, pharmacokinetics and pharmacodynamics properties were examined to narrow down the screened compounds. This analysis yielded a hit molecule, DB03916 that exhibited a better docking score, higher binding affinity and better drug-like properties in contrast to the reference compound that suffers from a toxicity property. Importantly, the result was validated using a 50ns molecular dynamics simulation study. Overall, we conclude that the identified hit molecule DB03916 is believed to serve as a prospective antagonist against VPS34 for cancer treatment.

The impact of autophagy during the development and survival of glioblastoma.

Glioblastoma is the most common and aggressive adult brain tumour, with poor median survival and limited treatment options. Following surgical resection and chemotherapy, recurrence of the disease is inevitable. Genomic studies have identified key drivers of glioblastoma development, including amplifications of receptor tyrosine kinases, which drive tumour growth. To improve treatment, it is crucial to understand survival response processes in glioblastoma that fuel cell proliferation and promote resistance to treatment. One such process is autophagy, a catabolic pathway that delivers cellular components sequestered into vesicles for lysosomal degradation. Autophagy plays an important role in maintaining cellular homeostasis and is upregulated during stress conditions, such as limited nutrient and oxygen availability, and in response to anti-cancer therapy. Autophagy can also regulate pro-growth signalling and metabolic rewiring of cancer cells in order to support tumour growth. In this review, we will discuss our current understanding of how autophagy is implicated in glioblastoma development and survival. When appropriate, we will refer to findings derived from the role of autophagy in other cancer models and predict the outcome of manipulating autophagy during glioblastoma treatment.

The Role of Autophagy and NLRP3 Inflammasome in Liver Fibrosis.

Liver fibrosis is an intrinsic repair process of chronic injury with excessive deposition of extracellular matrix. As an early stage of various liver diseases, liver fibrosis is a reversible pathological process. Therefore, if not being controlled in time, liver fibrosis will evolve into cirrhosis, liver failure, and liver cancer. It has been demonstrated that hepatic stellate cells (HSCs) play a crucial role in the formation of liver fibrosis. In particular, the activation of HSCs is a key step for liver fibrosis. Recent researches have suggested that autophagy and inflammasome have biological effect on HSC activation. Herein, we review current studies about the impact of autophagy and NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome on liver fibrosis and the underlying mechanisms.

The impact of autophagy on arbovirus infection of mosquito cells.

Macroautophagy is an evolutionarily conserved cellular process critical for maintaining cellular homeostasis. It can additionally function as an innate immune response to viral infection as has been demonstrated for a number of arthropod-borne (arbo-) viruses. Arboviruses are maintained in a transmission cycle between vertebrate hosts and invertebrate vectors yet the majority of studies assessing autophagy-arbovirus interactions have been limited to the mammalian host. Therefore we evaluated the role of autophagy during arbovirus infection of the invertebrate vector using the tractable Aag2 Aedes aegypti mosquito cell culture system. Our data demonstrates that autophagy is significantly induced in mosquito cells upon infection with two divergent arboviruses: dengue virus-2 (DENV-2; Flaviviridae, Flavivirus) and chikungunya virus (CHIKV; Togaviridae, Alphavirus). While assessing the role of autophagy during arbovirus infection, we observed a somewhat paradoxical outcome. Both induction and suppression of autophagy via torin-1 and spautin-1, respectively, resulted in increased viral titers for both viruses, yet suppression of autophagy-related genes had no effect. Interestingly, chemical modulators of autophagy had either no effect or opposite effects in another widely used mosquito cell line, C6/36 Aedes albopictus cells. Together, our data reveals a limited role for autophagy during arbovirus infection of mosquito cells. Further, our findings suggest that commonly used chemical modulators of autophagy alter mosquito cells in such a way as to promote viral replication; however, it is unclear if this occurs directly through autophagic manipulation or other means.

Impact of Autophagy on Gene Expression and Tapetal Programmed Cell Death During Pollen Development in Rice.

Autophagy has recently been shown to be required for tapetal programmed cell death (PCD) and pollen maturation in rice. A transcriptional regulatory network is also known to play a key role in the progression of tapetal PCD. However, the relationship between the gene regulatory network and autophagy in rice anther development is mostly unknown. Here, we comprehensively analyzed the effect of autophagy disruption on gene expression profile during the tapetal PCD in rice anther development using high-throughput RNA sequencing. Expression of thousands of genes, including specific transcription factors and several proteases required for tapetal degradation, fluctuated synchronously at specific stages during tapetal PCD progression in the wild-type anthers, while this fluctuation showed significant delay in the autophagy-deficient mutant Osatg7-1. Moreover, gene ontology enrichment analysis in combination with self-organizing map clustering as well as pathway analysis revealed that the expression patterns of a variety of organelle-related genes as well as genes involved in carbohydrate/lipid metabolism were affected in the Osatg7-1 mutant during pollen maturation. These results suggest that autophagy is required for proper regulation of gene expression and quality control of organelles and timely progression of tapetal PCD during rice pollen development.

Impact of Autophagy and Aging on Iron Load and Ferritin in Drosophila Brain.

Biometals such as iron, copper, potassium, and zinc are essential regulatory elements of several biological processes. The homeostasis of biometals is often affected in age-related pathologies. Notably, impaired iron metabolism has been linked to several neurodegenerative disorders. Autophagy, an intracellular degradative process dependent on the lysosomes, is involved in the regulation of ferritin and iron levels. Impaired autophagy has been associated with normal pathological aging, and neurodegeneration. Non-mammalian model organisms such as Drosophila have proven to be appropriate for the investigation of age-related pathologies. Here, we show that ferritin is expressed in adult Drosophila brain and that iron and holoferritin accumulate with aging. At whole-brain level we found no direct relationship between the accumulation of holoferritin and a deficit in autophagy in aged Drosophila brain. However, synchrotron X-ray spectromicroscopy revealed an additional spectral feature in the iron-richest region of autophagy-deficient fly brains, consistent with iron–sulfur. This potentially arises from iron–sulfur clusters associated with altered mitochondrial iron homeostasis.

Blood autophagy defect causes accelerated non-hematopoietic organ aging.

Autophagy has been well studied in regulating aging; however, the impact of autophagy in one organ on the aging of other organs has not been documented. In this study, we used a mouse model with deletion of an autophagy-essential gene Atg7 in hematopoietic system to evaluate the intrinsic role of hematopoietic autophagy on the aging of non-hematopoietic organs. We found that autophagy defect in hematopoietic system causes growth retardation and shortened lifespan, along with aging-like phenotypes including hypertrophic heart, lung and spleen, but atrophic thymus and reduced bone mineral density at organismal level. Hematopoietic autophagy defect also causes increased oxidative stress and mitochondrial mass or aging gene expression at cellular level in multiple non-hematopoietic organs. The organ aging in the Atg7-deleted mice was reversed by anatomic connection to wild-type mice with intact blood autophagy via parabiosis, but not by injection of blood cell-free plasma. Our finding thus highlights an essential role of hematopoietic autophagy for decelerating aging in non-hematopoietic organs.

Autophagy: New Insights into Mechanisms of Action and Resistance of Treatment in Acute Promyelocytic leukemia.

Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all-trans retinoid acid (ATRA)—a differentiating agent currently used in clinical settings—restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL.

Protective roles of autophagy in sepsis‐induced skeletal muscle dysfunction, metabolic derangements and mortality

RationaleSepsis‐induced skeletal muscle dysfunction contributes to physical disability, and increased mortality in intensive care unit patients. Autophagy is a catabolic process by which cells degrade their own components. Recent studies indicate that sepsis triggers sustained induction of autophagy in skeletal muscles; however, the impact of autophagy on sepsis‐induced contractile and metabolic dysfunctions remains unclear. In this study, we evaluated the functional importance of autophagy in sepsis‐induced skeletal muscle dysfunction.MethodsSelective inhibition of autophagy in skeletal muscles was accomplished by cross breeding floxed Atg7 mice (Atg7f/f) with those expressing HSA‐Cre‐ERT2. Cre induction was achieved by feeding Tamoxifen. Control mice were Atg7f/f‐HSA‐Cre‐ERT2 without Tamoxifen feeding. Sepsis was induced by the cecal ligation and perforation (CLP) procedure and animals were examined after 48 and 144 hours of sepsis. Animals undergoing sham procedure served as control.ResultsDeletion of Atg7 in skeletal muscle had a major impact on sepsis‐induced loss of body weight and muscle mass as indicated by worsening of body weight loss, more severe sepsis‐induced skeletal muscle atrophy and further decline in muscle contractility in mice with Atg7 deletions vs. those with intact Atg7 undergoing sepsis for 48 hours. In additions, body weight loss, hypoglycaemia and mortality were more severe over a 144 hours period in mice with Atg7 deletion as compared to those with intact Atg7. These results suggest that induction of autophagy in septic skeletal muscles play a protective role against sepsis‐induced mortality. Furthermore, sepsis had no major effect on limb muscle mitochondrial respiration in animals with intact muscle Atg7 while those with deleted muscle Atg7 showed significant impairments of limb muscle mitochondrial respiration both in the sham and septic conditions. Finally, significant upregulation of ubiquitin E3 ligases (Atrogin‐1 and MuRF1) was observed in septic muscles. Deletion of muscle Atg7 had no effect on this response when measured after 48 hours of sepsis.ConclusionWe conclude that autophagy plays a protective role by preserving muscle mitochondrial quality and function and that autophagy inhibition in skeletal muscles worsens sepsis‐induced loss of body weight and muscle atrophy possibly due to exaggerated responses to catabolic stimuli triggered by sepsis. Our results also indicate that autophagy in septic skeletal muscles play a protective role against sepsis‐induced metabolic derangements and mortality.Support or Funding InformationThis study is funded by grants from the Canadian Institutes of Health Research. Gilles Gouspillou salary support is provided by a FQRS Chercheur Boursier Junior 1 Award. Jean‐Philippe Leduc‐Gaudet is supported by CIHR Vanier Doctoral Scholarship.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Alzheimer's Disease Presenilin-1 Mutation Sensitizes Neurons to Impaired Autophagy Flux and Propofol Neurotoxicity: Role of Calcium Dysregulation.

Disruption of intracellular Ca2+ homeostasis and associated autophagy dysfunction contribute to neuropathology in Alzheimer's disease (AD). To study the effects of propofol on cell viability via its effects on intracellular Ca2+ homeostasis, and the impact of autophagy, in a neuronal model of presenilin-mutated familial AD (FAD). We treated PC12 cells, stably transfected with either mutated presenilin-1 (L286V) or wild type (WT) controls, with propofol at different doses and durations, in the presence or absence of extracellular Ca2+, antagonists of inositol trisphosphate receptors (InsP3R, xestospongin C) and/or ryanodine receptors (RYR, dantrolene), or an inhibitor of autophagy flux (Bafilomycin). We determined cell viability, cytosolic Ca2+ concentrations ([Ca2+]c), vATPase protein expression, and lysosomal acidification. The propofol dose- and time-dependently decreased cell viability significantly more in L286V than WT cells, especially at the pharmacological dose (>50μM), and together with bafilomycin (40 nM). Clinically used concentrations of propofol (<20μM) tended to increase cell viability. Propofol significantly increased [Ca2+]c more in L286V than in WT cells, which was associated with decrease of vATPase expression and localization to the lysosome. Both toxicity and increased Ca2+ levels were ameliorated by inhibiting InsP3R/RYR. However, the combined inhibition of both receptors paradoxically increased [Ca2+]c, by inducing Ca2+ influx from the extracellular space, causing greater cytotoxicity. Impairment in autophagy function acts to deteriorate cell death induced by propofol in FAD neuronal cells. Cell death is ameliorated by either RYR or InsP3R antagonists on their own, but not when both are co-administered.

Inhibition of autophagy promoted high glucose/ROS-mediated apoptosis in ADSCs

BackgroundIncreased apoptosis in adipose tissue-derived stem cells (ADSCs) limits their application in treating diabetes complications. Autophagy is a molecular process that allows cells to degrade and recover damaged macromolecules, and closely interacts with apoptosis. The aim of the present study was to investigate the potential role of autophagy in ADSC apoptosis induced by high glucose.MethodsHuman ADSCs were cultured in normal or high-glucose medium for 6 h, 12 h, or 24 h. The effects of high glucose on ADSC autophagy, reactive oxygen species (ROS) production, and apoptosis were evaluated. The impact of autophagy on ROS production and apoptosis was explored by treatment with rapamycin or 3-methyladenine (3-MA). The c-jun kinase (JNK) signaling pathway was investigated by pharmacological disruption of SP600125.ResultsADSCs subjected to high glucose stress showed an obvious induction of autophagy and apoptosis and a significant increase in intracellular ROS levels. The JNK signaling pathway was confirmed to be involved in high glucose-induced autophagy. Pre-treatment with SP600125 or N-acetylcysteine reversed the effects of high glucose on the JNK signaling pathway and autophagy-related proteins. Pretreatment of ADSCs with 3-MA under high glucose stress induced a further increase in ROS levels compared to those of high glucose-treated cells. Furthermore, ADSCs pretreated with 3-MA under high glucose stress showed a marked increase in apoptosis compared with that of the cells treated with high glucose. Conversely, pre-treatment with rapamycin inhibited the apoptosis of ADSCs.ConclusionsTaken together, our data suggest that autophagy may play a protective role in high glucose-induced apoptosis in ADSCs. ROS/JNK signaling is essential in upregulating high glucose-induced autophagy. This study provides new insights into the molecular mechanism of autophagy involved in high glucose-induced apoptosis in ADSCs.

A LINK BETWEEN AUTOPHAGY REGULATORY PROTEINS M-TOR AND BECLIN-1 AND PARAMETERS OF LYMPHOGENIC METASTASIS IN COLORECTAL CANCER

Currently the impact of autophagy on carcinogenesis remains understudied. On the one hand, autophagy acts as a tumor suppressor, as it activates degradation of oncoproteins, toxic proteins, and damaged cell organelles, that may be aggressive and lead to DNA damage. On the other hand, autophagy may promote tumor cell survival under hypoxia and in the presence of reactive oxygen species, which occurs primarily due to blocking of apoptosis mechanisms, raising the chances for maintaining tumor clone dynamics. Autophagy regulation is a complicated and multi-stage process. The main regulator here is a signaling pathway that activates serine/threonine protein kinase m-TOR (the mammalian target of rapamycin). Data on the impact of autophagic proteins ATG5, LC3A, LC3B, and Beclin-1 on malignant cell survival as well as on tumor growth and progression have been reported in literature. However, studies aimed at seeking possible relationships between autophagy and pathogenetic mechanisms of carcinogenesis are of great interest.Theaimof the study is to investigate a relationship between the expression parameters of autophagy regulatory proteins m-TOR and Beclin-1 and the features of lymphogenic metastasis in colorectal cancer.Materials and methods. The study included 105 patients with T1-4N0-3M0 colorectal cancer treated in the Thoracic and Abdominal Department of Cancer Research Institute of Tomsk Research Medical Center from 2012 to 2015. The average age of patients was 59.7±4.3 years. Morphological verification of the diagnosis was performed on the biopsy samples of primary tumor tissue. Staging of colorectal cancer was determined according to the TNM classification of malignant tumors (2002).Results.Analysis of the frequency of lymphogenic metastasis depending on the presence or absence of m-Tor and Beclin-1 expression in tumor cell cytoplasm revealed a statistically significant link between these variables.Conclusion.The obtained findings clearly exhibit that deceleration or loss of autophagic activity in the tumor is accompanied by implementation of lymphogenic dissemination, which is a predictor of an unfavorable outcome of the disease.