Dual Role Of Autophagy Research Articles

Occurrence of autophagy during pioneer root and stem development in Populus trichocarpa

Main conclusionAutophagy is involved in developmentally programmed cell death and is identified during the early development of phloem, as well as xylem with a dual role, as both an inducer and executioner of cell death.The regulation of primary and secondary development of roots and stems is important for the establishment of root systems and for the overall survival of trees. The molecular and cellular basis of the autophagic processes, which are used at distinct moments during the growth of both organs, is crucial to understand the regulation of their development. To address this, we use Populus trichocarpa seedlings grown in a rhizotron system to examine the autophagy processes involved in root and stem development. To monitor the visual aspects of autophagy, transmission electron microscopy (TEM) and immunolocalization of AuTophaGy-related protein (ATG8) enabled observations of the phenomenon at a structural level. To gain further insight into the autophagy process at the protein and molecular level, we evaluated the expression of ATG gene transcripts and ATG protein levels. Alternations in the expression level of specific ATG genes and localization of ATG8 proteins were observed during the course of root or stem primary and secondary development. Specifically, ATG8 was present in the cells exhibiting autophagy, during the differentiation and early development of xylem and phloem tissues, including both xylary and extraxylary fibers. Ultrastructural observations revealed tonoplast invagination with the formation of autophagic-like bodies. Additionally, the accumulation of autophagosomes was identifiable during the differentiation of xylem in both organs, long before the commencement of cell death. Taken together, these results provide evidence in support of the dual role of autophagy in developmental PCD. A specific role of the controller of cell death, which is a committed step with the release of hydrolytic enzymes from the vacuole and final digestion of protoplast, from which there is no return once initiated, is only attributed to mega-autophagy.

TGFB1-induced autophagy affects the pattern of pancreatic cancer progression in distinct ways depending on SMAD4 status

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Given that macroautophagy/autophagy activation is prevalent in PDAC, the dual roles of autophagy could be involved in PDAC heterogeneity. In this work, we demonstrated that TGFB1 induced autophagic flux through SMAD4-dependent or SMAD4-independent pathways based on a distinct genetic context. In SMAD4-positive PDAC cells, TGFB1-induced autophagy promoted proliferation and inhibited migration by decreasing the nuclear translocation of SMAD4. Conversely, TGFB1-induced autophagy inhibited proliferation and promoted migration in SMAD4-negative cells through the regulation of MAPK/ERK activation. TGFB1 expression also positively correlated with LC3B expression in PDAC specimens. A high level of LC3B was associated with unfavorable overall survival (OS) and disease-free survival (DFS) in SMAD4-negative PDAC patients, although LC3B could not predict OS and DFS for the 110 PDAC patients. Thus, TGFB1-induced autophagy contributed to the different patterns of PDAC progression. This knowledge can aid in improving our understanding of the molecular classification of PDAC and might guide the development of therapeutic strategies for PDAC, especially for SMAD4-negative PDAC. Abbreviations CDH1: cadherin 1; CDH2: cadherin 2; CI: combination index; CQ: chloroquine; DFS: disease-free survival; EMT: epithelial-to-mesenchymal transition; ERK: extracellular signal-regulated protein kinase; GFP: green fluorescent protein; IHC: immunohistochemistry; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK: mitogen-activated protein kinase; OS: overall survival; PBS: phosphate-buffered saline; PDAC: pancreatic ductal adenocarcinoma; RAP: rapamycin; RFP: red fluorescent protein; RT: room temperature; shRNA: short-hairpin RNA; SQSTM1: sequestosome 1; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TGFB1: transforming growth factor beta 1; TMA: tissue microarray

Dual Role of Autophagy in Diseases of the Central Nervous System.

Autophagy is a vital lysosomal degradation and recycling pathway in the eukaryotic cell, responsible for maintaining an intricate balance between cell survival and cell death, necessary for neuronal survival and function. This dual role played by autophagy raises the question whether this process is a protective or a destructive pathway, the contributor of neuronal cell death or a failed attempt to repair aberrant processes? Deregulated autophagy at different steps of the pathway, whether excessive or downregulated, has been proposed to be associated with neurodegenerative disorders such as Alzheimer’s-, Huntington’s-, and Parkinson’s-disease, known for their intracellular accumulation of protein aggregates. Recent observations of impaired autophagy also appeared in psychiatric disorders such as schizophrenia and bipolar disorder suggesting an additional contribution to the pathophysiology of mental illness. Here we review the current understanding of autophagy’s role in various neuropsychiatric disorders and, hitherto, the prevailing new potential autophagy-related therapeutic strategies for their treatment.

Abstract P1-01-12: Expression of autophagy related genes impacts clinical outcomes of human breast carcinoma and is associated with estrogen and progestin receptor status

Abstract The dual role of autophagy in breast cancer initiation, progression and responsiveness to various therapies is the focus of extensive studies. Our goal is to assess the relationship of expression of certain autophagy related genes in primary breast carcinomas to predict risk of recurrence. Our hypothesis includes the caveat that unique gene expression subsets will be deciphered by utilizing Laser Capture Microdissected breast carcinoma cells from tissue biopsies containing many cell types. Methods: Comprehensive analyses of de-identified biomarker results, characteristics of 247 breast carcinoma specimens and clinical outcomes were performed by univariable Cox regressions, Kaplan Meier plots and LASSO with R software version 3.2.5. Microarray analyses were performed on RNA isolated from LCM-procured carcinoma cells to identify gene signatures associated with breast cancer behavior. Results: Expression levels of 22 autophagy related genes analyzed by univariable Cox regression revealed that RB1CC1, KEAP1, ATG7, RUBCN, NOD2, HMOX1, BECN1, PIK3R4 were significant for predicting Progression Free Survival (PFS) at the discovery level of the adjusted p-value < 0.3. Of these, RB1CC1, KEAP1, & ATG7 were significant for Overall Survival (OS) without regard to ER/PR status. Using Kaplan Meier analyses, expression levels of each of 10 candidate genes predicted PFS of which expression of 6 of these genes also predicted OS using a median split cutoff without regard to ER/PR status. Applying LASSO computations without regard to ER/PR status of the primary breast cancer, a clinically relevant gene expression profile consisting of ATG7, BCL2, HMOX1, KEAP1, NOD2, PTEN, RB1CC1, and ULK4 predicted PFS. Collectively, expression of these 8 genes with TP53 and RUBCN predicted OS without regard to ER/PR status. Violin plots of relative gene expression of each of the 22 candidate genes known to be associated with autophagy pathways revealed that ATG7, ATG12, BCL2 and BECN1 were elevated in ER+ lesions while BCL2 and BECN1 were also elevated in PR+ breast carcinomas. Expression levels of 16 of the 22 autophagy related genes examined by univariable Cox regression were related to either ER or PR status of the primary lesion and predicted either PFS or OS. Refinement of clinically relevant gene subsets was accomplished by LASSO calculations in which either the ER or PR protein status of the primary breast carcinoma was considered. Of the genes in the molecular signatures derived, expression levels in breast carcinomas separated by either ER or PR status of the lesion were tested by Kaplan Meier analyses to assess relationships to PFS and OS. Conclusions: Using gene expression results derived from microarray analyses of LCM-procured breast carcinoma cells of primary lesions, subsets of autophagy related genes were identified that predict a patient's risk of recurrence and overall survival. Expression of a number of candidate genes appears to be related to either/both the ER or PR protein status of the primary lesion. Collectively, results suggest that expression of certain autophagy related genes may serve as biomarkers for assessing prognosis of breast carcinoma thus impacting clinical management of breast cancer. Citation Format: Wittliff JL, Hameed ZR, Daniels MW, Cheng A. Expression of autophagy related genes impacts clinical outcomes of human breast carcinoma and is associated with estrogen and progestin receptor status [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-12.

Mechanism and Regulation of Autophagy in Cancer

Autophagy, or self-eating, is a catabolic process that plays a crucial role in cellular homeostasis by carrying out bulk degradation of defective or superfluous proteins as well as worn-out organelles through a specialized structure, the autophagosome, which in turn fuses with the lysosome. Autophagy also alleviates cellular stress induced by nutrient deprivation, metabolic disturbance, hypoxia, and the like, by recycling intracellular constituents. This role of autophagy, to provide metabolic precursors especially upon starvation, might also contribute to the survival of cancer cells. The role of autophagy in cancer cells is ambiguous given that its downregulation or upregulation has been observed to depend on cancer stage and pathological grade. Autophagy has been found to exhibit a dual effect on tumorigenesis where it functions to suppress tumor progression by eliminating factors that cause genome instability while promoting survival of cancer cells under unfavorable conditions like therapeutic stress. This review aims to explain the mechanism, regulation, and the dual role of autophagy in cancer.

Regulatory effects of traditional Chinese medicine on autophagy in myocardial ischemia reperfusion injury

Autophagy is a basic process of eliminating unnecessary or damaged organelles by lysosome to maintain the internal environment homeostasis. Recent studies have revealed that autophagy plays an important role in pathology of myocardial ischemia reperfusion. In the phase of ischemia, moderate autophagy can protect the cells against various stress; but in the phase of reperfusion, excessive autophagy can increase the death of cells. Therefore, the dual role of autophagy in myocardial ischemia reperfusion provides a new therapeutic target for the treatment of heart disease. In recent years, more and more Chinese medicines have been proved to adjust the autophagy in myocardial cells, and protect the damaged myocardium by enhancing or inhibiting autophagy. This article would review the molecular mechanisms of autophagy and its role in myocardial ischemia reperfusion injury as well as the regulation effect of Chinese medicine on it.

Survival or death: a dual role for autophagy in stress-induced pericyte loss in diabetic retinopathy.

Aims/hypothesisIntra-retinal extravasation and modification of LDL have been implicated in diabetic retinopathy: autophagy may mediate these effects.MethodsImmunohistochemistry was used to detect autophagy marker LC3B in human and murine diabetic and non-diabetic retinas. Cultured human retinal capillary pericytes (HRCPs) were treated with in vitro-modified heavily-oxidised glycated LDL (HOG-LDL) vs native LDL (N-LDL) with or without autophagy modulators: green fluorescent protein–LC3 transfection; small interfering RNAs against Beclin-1, c-Jun NH(2)-terminal kinase (JNK) and C/EBP-homologous protein (CHOP); autophagy inhibitor 3-MA (5 mmol/l) and/or caspase inhibitor Z-VAD-fmk (100 μmol/l). Autophagy, cell viability, oxidative stress, endoplasmic reticulum stress, JNK activation, apoptosis and CHOP expression were assessed by western blots, CCK-8 assay and TUNEL assay. Finally, HOG-LDL vs N-LDL were injected intravitreally to STZ-induced diabetic vs control rats (yielding 50 and 200 mg protein/l intravitreal concentration) and, after 7 days, retinas were analysed for ER stress, autophagy and apoptosis.ResultsIntra-retinal autophagy (LC3B staining) was increased in diabetic vs non-diabetic humans and mice. In HRCPs, 50 mg/l HOG-LDL elicited autophagy without altering cell viability, and inhibition of autophagy decreased survival. At 100–200 mg/l, HOG-LDL caused significant cell death, and inhibition of either autophagy or apoptosis improved survival. Further, 25–200 mg/l HOG-LDL dose-dependently induced oxidative and ER stress. JNK activation was implicated in autophagy but not in apoptosis. In diabetic rat retina, 50 mg/l intravitreal HOG-LDL elicited autophagy and ER stress but not apoptosis; 200 mg/l elicited greater ER stress and apoptosis.ConclusionsAutophagy has a dual role in diabetic retinopathy: under mild stress (50 mg/l HOG-LDL) it is protective; under more severe stress (200 mg/l HOG-LDL) it promotes cell death.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4058-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Abstract 2910: The dual role of autophagy in cadmium induced prostate carcinogenesis

Abstract Cadmium chloride (Cd) and cadmium products cause both acute and chronic cytotoxicity and Cd exposure correlates with the risk of cancer, especially prostate cancer in humans. On the cellular and molecular level, Cd compounds may promote transformation of healthy cells to a malignant state by inducing expression of pro-survival signaling molecules. However, the precise molecular mechanism by which Cd affects cellular transformation in different tissue types, especially in prostate, is yet to be delineated. Autophagy is an intracellular lysosomal degradation process by which cells remove damaged organelles and maintain the integrity of intracellular components. In cancer cells, autophagy promotes cancer cell survival as well as cell death. It is unclear of how, and under what circumstances, these dual and opposite roles of autophagy affect both anti-oncogenic and oncogenic functions. It is possible that uncharacterized molecular switch that influences the anti-oncogenic function of autophagy in healthy cells to become oncogenic. In our studies, we found that exposure of normal prostate epithelial cells (RWPE-2) in culture to Cd (10μM) results in growth inhibition. By contrast, the growth of Cd-transformed prostate epithelial (CTPE) cells was not inhibited by the same Cd treatment. While analyzing the molecular link between Cd induced toxicity and generation of reactive oxygen species (ROS) generation in RWPE-2 and CTPE cells; we found there was no significant change in the ROS induction in both cell types. In addition, no changes in the expression of autophagy targeted genes (Atg family proteins) were seen in Cd treated in both non-transformed and transformed cells. However, microtubule-associated protein 1A/1B-light chain 3B (LC-3B), which is directly involved in autophagy initiation was upregulated in Cd-treated non-transformed cells, but not in Cd-treated transformed cells. LC-3B activation also correlated with growth inhibition in non-transformed cells, while impairing LC-3B activation in RWPE-2 cells causes resistance to CD induced growth inhibition. Our ongoing study will determine whether induction of autophagy via LC-3B is a key event that facilitates Cd-mediated conversion of non-transformed prostate epithelial cells to a malignant state. We strongly believe our studies will define a new concept of LC-3B mediated autophagy in Cd-induced prostate carcinogenesis. Citation Format: Trinath P. Das, Arokya MS John, Suman Suman, Murali Ankem, Chendil Damodaran. The dual role of autophagy in cadmium induced prostate carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2910. doi:10.1158/1538-7445.AM2015-2910

Dual role of autophagy in cancer

Dual role of autophagy in cancer

Dual role of autophagy in chronic myeloid leukemia

Autophagy is a lysosome-mediated self-degradation process that mediates degradation and recycling of all major components of eukaryotic cells to maintain intracellular homeostasis. Autophagy is associated with leukemo-genesis, treatment, drug-resistance and recurrence of chronic myeloid leukemia (CML). Autophagy is a double-edged sword which has dual characteristics to promote survival and death of CML cells. Thus exploring different roles of autophagy under different conditions, finding out different autophagy pathways and combination with autophagy inducer or inhibitor of autophagy is of great importance to improve therapeutic effect, overcome drug-resistance and recurrence and finally come to a cure. This article makes a summary on the dual role of autophagy in CML.

The divergent roles of autophagy in ischemia and preconditioning

Autophagy is an evolutionarily conserved and lysosome-dependent process for degrading and recycling cellular constituents. Autophagy is activated following an ischemic insult or preconditioning, but it may exert dual roles in cell death or survival during these two processes. Preconditioning or lethal ischemia may trigger autophagy via multiple signaling pathways involving endoplasmic reticulum (ER) stress, AMPK/TSC/mTOR, Beclin 1/BNIP3/SPK2, and FoxO/NF-κB transcription factors, etc. Autophagy then interacts with apoptotic and necrotic signaling pathways to regulate cell death. Autophagy may also maintain cell function by removing protein aggregates or damaged mitochondria. To date, the dual roles of autophagy in ischemia and preconditioning have not been fully clarified. The purpose of the present review is to summarize the recent progress in the mechanisms underlying autophagy activation during ischemia and preconditioning. A better understanding of the dual effects of autophagy in ischemia and preconditioning could help to develop new strategies for the preventive treatment of ischemia.

Key autophagic targets and relevant small-molecule compounds in cancer therapy.

Autophagy is a highly conserved lysosomal degradation process which can recycle unnecessary or dysfunctional cell organelles and proteins, thereby playing a crucial regulatory role in cell survival and maintenance. It has been widely accepted that autophagy regulates various pathological processes, among which cancer attracts much attention. Autophagy may either promote cancer cell survival by providing energy during unfavourable metabolic circumstance or can induce individual cancer cell death by preventing necrosis and increasing genetic instability. Thus, dual roles of autophagy may determine the destiny of cancer cells and make it an attractive target for small-molecule drug discovery. Collectively, key autophagy-related elements as potential targets, oncogenes mTORC1, class I PI3K and AKT, as well as tumour suppressor class III PI3K, Beclin-1 and p53, have been discussed. In addition, some small molecule drugs, such as rapamycin and its derivatives, rottlerin, PP242 and AZD8055 (targeting PI3K/AKT/mTORC1), spautin-1, and tamoxifen, as well as oridonin and metformin (targeting p53), can modulate autophagic pathways in different types of cancer. All these data will shed new light on targeting the autophagic process for cancer therapy, using small-molecule compounds, to fight cancer in the near future.

Autophagy regulates the cell cycle of murine HSPCs in a nutrient-dependent manner

Autophagy is implicated in hematopoiesis, but its role in the regulation of the hematopoietic stem and progenitor cell (HSPC) cycle remains obscure. Here, we show that autophagy is essential to maintain and regulate the cell cycle of HSPCs in a nutrient-dependent manner. The loss of autophagy via conditional deletion of its essential gene atg7 ablated the cell cycle of HSPCs. Under physiologic or nutrient-rich conditions, the in vivo activation of autophagy promoted the cell cycle entry of hematopoietic stem cells and upregulated cyclin D3 expression in HSPCs. In contrast, under poor nutrient conditions, the ex vivo inhibition of early, but not late, autophagy signaling events enhanced the G1/S transition of HSPCs. Cyclin D3 was downregulated in HSPCs in response to nutrient stress. A knockdown of cyclin D3 blocked the G1/S transition in HSPCs. Surprisingly, the ex vivo inhibition of starvation-induced early, but not late, autophagy signaling inhibited the ubiquitin-mediated degradation of cyclin D3 in HSPCs. Furthermore, a conditional autophagy defect also had this effect, leading to an elevated cyclin D3 level in these cells. This suggested a dependency of the proteasomal degradation of cyclin D3 on early, but not late, events in autophagy signaling under nutrient stress in HSPCs. Our results thus indicate a dual role of autophagy in the nutrient-dependent modulation of the cell cycle entry of hematopoietic stem cells and G1/S transition of HSPCs via the regulation of cyclin D3 to maintain a proper cell cycle in HSPCs and normal hematopoiesis during adult life.

Dual Role of Autophagy in Lipopolysaccharide-induced Preodontoblastic Cells

Odontoblasts derive from neural crest–derived odontogenic mesenchymal cells, and they are an important barrier of defense for the host. Survival and immunity of odontoblasts play important roles in protecting the dentin-pulp structure. Autophagy can eliminate damaged organelles and recycle cellular components to facilitate cellular homeostasis. Autophagy can be activated with external stressors, such as starvation, hypoxia, and infection. In this study, the role of autophagy in inflamed odontoblasts was explored, and its possible mechanism was investigated. Cell viability was not affected by mild lipopolysaccharide (LPS) stimulation, and autophagy was activated during this process. Immunofluorescence of light chain 3 confirmed that autophagy was induced with LPS treatment. Early-stage autophagy inhibition resulted in down-regulated cell viability, contrary to the up-regulated cell viability at late-stage autophagy inhibition. Western blot suggested that p-Akt and survivin were not activated in the early stage, and they gradually increased and peaked in the late stage. Meanwhile, autophagy was down-regulated through the Akt/mTOR/survivin pathway in the late stage. Thus, autophagy has a dual role in inflamed odontoblasts, which indicates its importance in maintaining the microenvironment homeostasis of odontoblasts. Autophagy was induced as a survival mechanism in the early stage, and it decreased through the Akt/mTOR/survivin signaling pathway in the late stage.

Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells

Ionizing radiation induces cellular senescence to suppress cancer cell proliferation. However, it also induces deleterious bystander effects in the unirradiated neighboring cells through the release of senescence-associated secretory phenotypes (SASPs) that promote tumor progression. Although autophagy has been reported to promote senescence, its role is still unclear. We previously showed that radiation induces senescence in PTTG1-depleted cancer cells. In this study, we found that autophagy was required for the radiation-induced senescence in PTTG1-depleted breast cancer cells. Inhibition of autophagy caused the cells to switch from radiation-induced senescence to apoptosis. Senescent cancer cells exerted bystander effects by promoting the invasion and migration of unirradiated cells through the release of CSF2 and the subsequently activation of the JAK2-STAT3 and AKT pathways. However, the radiation-induced bystander effects were correlated with the inhibition of endogenous autophagy in bystander cells, which also resulted from the activation of the CSF2-JAK2 pathway. The induction of autophagy by rapamycin reduced the radiation-induced bystander effects. This study reveals, for the first time, the dual role of autophagy in radiation-induced senescence and bystander effects.

Autophagy, plant senescence, and nutrient recycling

Large numbers of publications have appeared over the last few years, dealing with the molecular details of the regulation and process of the autophagy machinery in animals, plants, and unicellular eukaryotic organisms. This strong interest is caused by the fact that the autophagic process is involved in the adaptation of organisms to their environment and to stressful conditions, thereby contributing to cell and organism survival and longevity. In plants, as in other eukaryotes, autophagy is associated with longevity as mutants display early and strong leaf senescence symptoms, however, the exact role of autophagy as a pro-survival or pro-death process is unclear. Recently, evidence that autophagy participates in nitrogen remobilization has been provided, but the duality of the role of autophagy in leaf longevity and/or nutrient recycling through cell component catabolism remains. This review aims to give an overview of leaf senescence-associated processes from the physiological point of view and to discuss relationships between nutrient recycling, proteolysis, and autophagy. The dual role of autophagy as a pro-survival or pro-death process is discussed.

57: Positron emission tomography (PET) isotope production from laser-driven proton

The role of autophagy in radiation response of tumors remains largely elusive. By using a dual pharmacological and genetic inhibitory approach, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. First, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagyinhibition potentiated the tumour growthinhibitory effect of radiotherapy). Secondly, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers.

A dual role for autophagy in a murine model of lung cancer

Autophagy is a mechanism by which starving cells can control their energy requirements and metabolic states, thus facilitating the survival of cells in stressful environments, in particular in the pathogenesis of cancer. Here we report that tissue-specific inactivation of Atg5, essential for the formation of autophagosomes, markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage of tumour-bearing mice. Autophagy-defective lung cancers exhibit impaired mitochondrial energy homoeostasis, oxidative stress and a constitutively active DNA damage response. Genetic deletion of the tumour suppressor p53 reinstates cancer progression of autophagy-deficient tumours. Although there is improved survival, the onset of Atg5-mutant KRas(G12D)-driven lung tumours is markedly accelerated. Mechanistically, increased oncogenesis maps to regulatory T cells. These results demonstrate that, in KRas(G12D)-driven lung cancer, Atg5-regulated autophagy accelerates tumour progression; however, autophagy also represses early oncogenesis, suggesting a link between deregulated autophagy and regulatory T cell controlled anticancer immunity.

The dual role of autophagy in chondrocyte responses in the pathogenesis of articular cartilage degeneration in osteoarthritis

The present study aimed to analyze the responses to autophagy in osteoarthritis (OA) and aging chondrocytes in order to elucidate the role of autophagy in the pathogenesis of OA. We used multiple assays to confirm that autophagic activity was downregulated in chondrocytes of aged articular cartilage. Surprisingly, we found that the expression of autophagy-related proteins was not decreased in the tissues of patients with OA. We also observed that rapamycin-induced autophagy prevented the accumulation of subdiploid cells in young chondrocytes, while it induced cell death by autophagy in OA chondrocytes. Our results demonstrate that autophagic activity decreases with aging, and may be responsible for the cytoprotective effects in young cartilage. However, we found that autophagic activity in patients with OA was higher than in the aging group, and reported autophagic cell death in OA chondrocytes. These results suggest that autophagy plays both a cytoprotective and death-promoting role in the pathogenesis of OA.

Autophagy modulation as a target for anticancer drug discovery

Autophagy, an evolutionarily conserved catabolic process involving the engulfment and degradation of non-essential or abnormal cellular organelles and proteins, is crucial for homeostatic maintenance in living cells. This highly regulated, multi-step process has been implicated in diverse diseases including cancer. Autophagy can function as either a promoter or a suppressor of cancer, which makes it a promising and challenging therapeutic target. Herein, we overview the regulatory mechanisms and dual roles of autophagy in cancer. We also describe some of the representative agents that exert their anticancer effects by regulating autophagy. Additionally, some emerging strategies aimed at modulating autophagy are discussed as having the potential for future anticancer drug discovery. In summary, these findings will provide valuable information to better utilize autophagy in the future development of anticancer therapeutics that meet clinical requirements.