Simultaneous Detection of Autophagy and Epithelial to Mesenchymal Transition in the Non-small Cell Lung Cancer Cells

Alizadeh, Javad; Shojaei, Shahla; Sepanjnia, Adel; Hashemi, Mohammad; Eftekharpour, Eftekhar; Ghavami, Saeid

doi:10.1007/7651_2017_84

Cited by 29 publications

(26 citation statements)

References 70 publications

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“…This work clearly supports the published literature on the kidney, liver, and other organs, where it has been shown that autophagy regulates tissue fibrosis (32,33). However, it was recently reported that autophagy is a necessary mechanism for changing the phenotype of lung epithelial cells to mesenchymal cells (34,35); therefore, the present finding that shows incidence of autophagy in the epithelium of patients with asthma and HDM-challenged mice might confirm the role of EMT in the accumulation of mesenchymal cells in asthma pathogenesis.…”

Section: Discussionsupporting

confidence: 90%

Autophagy Activation in Asthma Airways Remodeling

McAlinden¹,

Deshpande

Ghavami

et al. 2019

Am J Respir Cell Mol Biol

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115

110

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Current asthma therapies fail to target airway remodeling that correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (hereinafter "autophagy") is a fundamental cell-recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and nonasthmatic lung tissues were histologically evaluated and were immunostained for key autophagy markers. The percentage area of positive staining was quantified in the epithelium and airway smooth muscle bundles using ImageJ software. Furthermore, the autophagy inhibitor chloroquine was tested intranasally in prophylactic (3 wk) and treatment (5 wk) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling, displaying thickened epithelium (P , 0.001) and reticular basement membrane (P , 0.0001), greater lamina propria depth (P , 0.005), and increased airway smooth muscle bundles (P , 0.001) with higher expression of Beclin-1 (P , 0.01) and ATG5 (autophagy-related gene 5) (P , 0.05) together with reduced p62 (P , 0.05) compared with nonasthmatic control tissues. Beclin-1 expression was significantly higher in asthmatic epithelium and ciliated cells (P , 0.05), suggesting a potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, airway hyperresponsiveness, and airway remodeling) of the autophagy inhibitor chloroquine. Our data demonstrate cell context-dependent and selective activation of autophagy in structural cells in asthma. Furthermore, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.

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Section: Discussionsupporting

confidence: 90%

Autophagy Activation in Asthma Airways Remodeling

McAlinden¹,

Deshpande

Ghavami

et al. 2019

Am J Respir Cell Mol Biol

Self Cite

115

110

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“…Autophagy degrades damaged organelles and allows misfolded proteins to be recycled in response to cellular stress and starvation, thereby suppressing tumor development in the early stages of cancers, whereas it improves tumor progression at advanced stages of tumor development via inducing resistance to chemotherapeutic agents [ 24 , 25 , 26 , 27 , 28 ]. The UPR is also activated in response to the accumulation of unfolded proteins in the ER [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Dastghaib

Shojaei

Mostafavi‐Pour

et al. 2020

Cells

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Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in GBM cells. Considering the role of the unfolded protein response (UPR) pathway in the regulation of autophagy, we investigated the involvement of UPR in Simva–TMZ-induced cell death by utilizing highly selective IRE1 RNase activity inhibitor MKC8866, PERK inhibitor GSK-2606414 (PERKi), and eIF2α inhibitor salubrinal. Simva–TMZ treatment decreased the viability of GBM cells and significantly increased apoptotic cell death when compared to TMZ or Simva alone. Simva–TMZ induced both UPR, as determined by an increase in GRP78, XBP splicing, eukaryote initiation factor 2α (eIF2α) phosphorylation, and inhibited autophagic flux (accumulation of LC3β-II and inhibition of p62 degradation). IRE1 RNase inhibition did not affect Simva–TMZ-induced cell death, but it significantly induced p62 degradation and increased the microtubule-associated proteins light chain 3 (LC3)β-II/LC3β-I ratio in U87 cells, while salubrinal did not affect the Simva–TMZ induced cytotoxicity of GBM cells. In contrast, protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibition significantly increased Simva–TMZ-induced cell death in U87 cells. Interestingly, whereas PERK inhibition induced p62 accumulation in both GBM cell lines, it differentially affected the LC3β-II/LC3β-I ratio in U87 (decrease) and U251 (increase) cells. Simvastatin sensitizes GBM cells to TMZ-induced cell death via a mechanism that involves autophagy and UPR pathways. More specifically, our results imply that the IRE1 and PERK signaling arms of the UPR regulate Simva–TMZ-mediated autophagy flux inhibition in U251 and U87 GBM cells.

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“…Autophagy is involved in a variety of physiological processes including cell differentiation and development, starvation and degradation of aberrant structures which ultimately maintains essential cellular homeostasis [62,63]. Physiologic autophagy plays beneficial roles on several basal cellular mechanisms in different organs through its intracellular catabolism activities, while pathological autophagy influences outcomes in disorders such as neurodegeneration, immunity, and cancer [59,[64][65][66][67][68][69]. Historically, research in the autophagy field was initiated by studies which characterized the lysosome; this led to our current knowledge about regulatory and molecular aspects of autophagy [70].…”

Section: Autophagymentioning

confidence: 99%

“…Macroautophagy was discovered in the late 1950s using morphological techniques [81]. Being a principle degrading mechanism of the cell, macroautophagy contributes to the survival of cells under stressful conditions [69,82]. Briefly, the cargo is sequestered into autophagosomes followed by their delivery to lysosomes for degradation [15].…”

Section: Macroautophagymentioning

confidence: 99%

The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections

Mehrbod¹,

et al. 2019

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Virus infection induces different cellular responses in infected cells. These include cellular stress responses like autophagy and unfolded protein response (UPR). Both autophagy and UPR are connected to programed cell death I (apoptosis) in chronic stress conditions to regulate cellular homeostasis via Bcl2 family proteins, CHOP and Beclin-1. In this review article we first briefly discuss arboviruses, influenza virus, and HIV and then describe the concepts of apoptosis, autophagy, and UPR. Finally, we focus upon how apoptosis, autophagy, and UPR are involved in the regulation of cellular responses to arboviruses, influenza virus and HIV infections.

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Simultaneous Detection of Autophagy and Epithelial to Mesenchymal Transition in the Non-small Cell Lung Cancer Cells

Cited by 29 publications

References 70 publications

Autophagy Activation in Asthma Airways Remodeling

Autophagy Activation in Asthma Airways Remodeling

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections

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