scholarly journals Concomitant and decoupled effects of cigarette smoke and SCAL1 upregulation on oncogenic phenotypes and ROS detoxification in lung adenocarcinoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Carmela Rieline V. Cruz ◽  
Jose Lorenzo M. Ferrer ◽  
Reynaldo L. Garcia
Keyword(s):  
Lung Cancer ◽  
Cigarette Smoke ◽  
Noncoding Rna ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Driver Mutations ◽  
Predisposing Factor ◽  
Alveolar Epithelial ◽  
Adenocarcinoma Cells ◽  
Dna Alterations

AbstractLung cancer is the leading cause of cancer deaths worldwide, with smoking as its primary predisposing factor. Although carcinogens in cigarettes are known to cause oncogenic DNA alterations, analyses of patient cohorts revealed heterogeneous genetic aberrations with no clear driver mutations. The contribution of noncoding RNAs (ncRNAs) in the pathogenesis of lung cancer has since been demonstrated. Their dysregulation has been linked to cancer initiation and progression. A novel long noncoding RNA (lncRNA) called smoke and cancer-associated lncRNA 1 (SCAL1) was recently found upregulated in smoke-exposed adenocarcinomic alveolar epithelial cells. The present study characterized the phenotypic consequences of SCAL1 overexpression and knockdown using A549 cells as model system, with or without prior exposure to cigarette smoke extract (CSE). Increase in SCAL1 levels either by CSE treatment or SCAL1 overexpression led to increased cell migration, extensive cytoskeletal remodeling, and resistance to apoptosis. Further, SCAL1 levels were negatively correlated with intracellular levels of reactive oxygen species (ROS). In contrast, SCAL1 knockdown showed converse results for these assays. These results confirm the oncogenic function of SCAL1 and its role as a CSE-activated lncRNA that mediates ROS detoxification in A549 cells, thereby allowing them to develop resistance to and survive smoke-induced toxicity.

Sodium tanshinone IIA sulfonate attenuates cigarette smoke extract-induced mitochondrial dysfunction, oxidative stress and apoptosis in alveolar epithelial cells by enhancing SIRT1 pathway

2021 ◽  
Author(s):  
Ruijuan Guan ◽  
Hongwei Yao ◽  
Ziying Li ◽  
Jing Qian ◽  
Liang Yuan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Mitochondrial Dysfunction ◽  
Cigarette Smoke ◽  
Mitochondrial Function ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Tanshinone Iia ◽  
Alveolar Epithelial ◽  
Sodium Tanshinone Iia Sulfonate

Abstract Emphysema is one of the most important phenotypes for chronic obstructive pulmonary disease (COPD). Apoptosis in alveolar epithelial cells (AECs) causes the emphysematous alterations in the smokers and patients with COPD. Sirtuin 1 (SIRT1) is able to attenuate mitochondrial dysfunction, oxidative stress, and to modulate apoptosis. It has been shown that sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, protects against cigarette smoke (CS)-induced emphysema/COPD in mice. However, the mechanisms underlying these findings remain unclear. Here, we investigate whether and how STS attenuates on AEC apoptosis via a SIRT1-dependent mechanism. We found that STS treatment decreased CS extract (CSE)-induced apoptosis in human alveolar epithelial A549 cells. STS reduced oxidative stress, improved mitochondrial function and mitochondrial membrane potential (ΔΨm), and restored mitochondrial dynamics-related protein expression. Moreover, STS promoted mitophagy, and increased oxidative phosphorylation (OXPHOS) protein levels (Complexes I-IV) in CSE-stimulated A549 cells. The protective effects of STS were associated with SIRT1 upregulation, since SIRT1 inhibition by EX 527 significantly attenuated or abolished the ability of STS to reverse the CSE-induced mitochondrial damage, oxidative stress, and apoptosis in A549 cells. In conclusion, STS ameliorates CSE-induced AEC apoptosis by improving mitochondrial function and reducing oxidative stress via enhancing SIRT1 pathway. These findings provide novel mechanisms underlying the protection of STS against CS-induced COPD.

scholarly journals Depression of lncRNA NEAT1 Antagonizes LPS-Evoked Acute Injury and Inflammatory Response in Alveolar Epithelial Cells via HMGB1-RAGE Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Hongchao Zhou ◽  
Xinhui Wang ◽  
Bin Zhang
Keyword(s):  
Noncoding Rna ◽  
Cell Injury ◽  
Alveolar Epithelial Cell ◽  
A549 Cells ◽  
High Mobility ◽  
Alveolar Epithelial Cells ◽  
Acute Injury ◽  
Mechanism Analysis ◽  
Alveolar Epithelial ◽  
Lactate Dehydrogenase Release

Sepsis-evoked acute lung injury (ALI) and its extreme manifestation, acute respiratory distress syndrome (ARDS), constitute a major cause of mortality in intensive care units. High levels of the long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) have been positively correlated with increased severity and unfavorable prognoses in patients with sepsis. Nevertheless, the function and molecular mechanism of NEAT1 in ALI remain elusive. In the current study, high levels of NEAT1 were confirmed in lipopolysaccharide- (LPS-) induced ALI mice models and in LPS-stimulated cells from the alveolar epithelial A549 cell line. Intriguingly, cessation of NEAT1 led to increased cell viability and decreased lactate dehydrogenase release, apoptosis, and caspase-3/9 activity, which conferred protection against LPS-induced injury in these cells. NEAT1 inhibition also restrained LPS-evoked transcripts and production of inflammatory cytokines IL-6, IL-1β, and TNF-α. A mechanism analysis corroborated the activation of high-mobility group box1 (HMGB1)/receptors for advanced glycation end products (RAGE) and NF-κB signaling in LPS-treated A549 cells. NEAT1 suppression reversed the activation of this pathway. Notably, reactivating HMGB1/RAGE signaling via HMGB1 overexpression blunted the anti-injury and anti-inflammation effects of NEAT1 knockdown. These findings suggest that NEAT1 may aggravate the progression of ALI and ARDS by inducing alveolar epithelial cell injury and inflammation via HMGB1/RAGE signaling, implying a promising treatment target for these conditions.

scholarly journals The Efficacy of Carotenoids in DNA Repair in Lung Cancer

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 99-99
Author(s):  
Junrui Cheng ◽  
Baxter Miller ◽  
Abdulkerim Eroglu
Keyword(s):  
Lung Cancer ◽  
Retinoic Acid ◽  
Cigarette Smoke ◽  
Genome Stability ◽  
Oxidative Dna Damage ◽  
Dna Lesions ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Lung Carcinoma Cells ◽  
Β Carotene

Abstract Objectives To explore the efficacy and mechanism of β-carotene, lycopene, and β-cryptoxanthin, three major carotenoids in cigarette smoking-induced oxidative DNA damage in lung carcinoma cells. We hypothesize that carotenoids reverse cigarette smoke-induced DNA lesions and genotoxic events, thereby playing a role in modulating genome stability. Methods We investigated mRNA and protein expressions of OGG1 in human alveolar epithelial cells exposed to cigarette smoke. Cells pre-treated with various doses of retinoic acid, β-carotene, lycopene, and β-cryptoxanthin for 24 hours, followed by being exposed to smoke using a smoking chamber. Results We found out that while retinoic acid, lycopene, and β-cryptoxanthin increased OGG1 expression at 10 nM and 100 nM, they led to a substantial decrease of OGG1 at 10μM. Intriguingly, at lower concentrations, lycopene treatment in smoking cells promoted OGG1 expression to an even greater extent compared with non-smoking cells, indicating that lycopene was effective in repairing DNA under oxidative stress. However, in smoking cells, the efficacy of β-cryptoxanthin in inducing OGG1 was not as profound as that in non-smoking cells. We are in the process of quantifying levels of 8-oxogunaine by HPLC-MS/MS. Conclusions While major carotenoids exerted an antioxidant at lower doses, they exerted a pro-oxidant effect at high doses. We believe that these novel findings will shed light on the mechanism of action of β-carotene, lycopene, and β-carotenoids at the molecular level for chemoprevention of lung cancer. Funding Sources USDA.

Alveolar epithelial cells type II show a high sensitivity to cigarette smoke extract

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
S Seehase ◽  
B Baron-Luehr ◽  
C Kugler ◽  
E Vollmer ◽  
T Goldmann
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
High Sensitivity ◽  
Cigarette Smoke Extract ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Alveolar Epithelial

scholarly journals Senescence associated long non-coding RNA 1 regulates cigarette smoke-induced senescence of type II alveolar epithelial cells through sirtuin-1 signaling

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098604
Author(s):  
Dong Yuan ◽  
Yuanshun Liu ◽  
Mengyu Li ◽  
Hongbin Zhou ◽  
Liming Cao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Sirtuin 1 ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Objective The primary aim of our study was to explore the mechanisms through which long non-coding RNA (lncRNA)-mediated sirtuin-1 (SIRT1) signaling regulates type II alveolar epithelial cell (AECII) senescence induced by a cigarette smoke-media suspension (CSM). Methods Pharmacological SIRT1 activation was induced using SRT2104 and senescence-associated lncRNA 1 (SAL-RNA1) was overexpressed. The expression of SIRT1, FOXO3a, p53, p21, MMP-9, and TIMP-1 in different groups was detected by qRT-PCR and Western blotting; the activity of SA-β gal was detected by staining; the binding of SIRT1 to FOXO3a and p53 gene transcription promoters was detected by Chip. Results We found that CSM increased AECII senescence, while SAL-RNA1 overexpression and SIRT1 activation significantly decreased levels of AECII senescence induced by CSM. Using chromatin immunoprecipitation, we found that SIRT1 bound differentially to transcriptional complexes on the FOXO3a and p53 promoters. Conclusion Our results suggested that lncRNA-SAL1-mediated SIRT1 signaling reduces senescence of AECIIs induced by CSM. These findings suggest a new therapeutic target to limit the irreversible apoptosis of lung epithelial cells in COPD patients.

scholarly journals Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1–7

2013 ◽  
Vol 305 (1) ◽  
pp. L33-L41 ◽  
Author(s):  
Bruce D. Uhal ◽  
Hang Nguyen ◽  
MyTrang Dang ◽  
Indiwari Gopallawa ◽  
Jing Jiang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Er Stress ◽  
Cathepsin D ◽  
Primary Cultures ◽  
A549 Cells ◽  
Surfactant Protein ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Induced Apoptosis ◽  
Jnk Activation

Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of angiotensin (ANG) II and its counterregulatory peptide ANG1–7. Mutations in surfactant protein C (SP-C) induce endoplasmic reticulum (ER) stress and apoptosis in AECs and cause lung fibrosis. This study tested the hypothesis that ER stress-induced apoptosis of AECs might also be regulated by the autocrine ANGII/ANG1–7 system of AECs. ER stress was induced in A549 cells or primary cultures of human AECs with the proteasome inhibitor MG132 or the SP-C BRICHOS domain mutant G100S. ER stress activated the ANGII-generating enzyme cathepsin D and simultaneously decreased the ANGII-degrading enzyme ACE-2, which normally generates the antiapoptotic peptide ANG1–7. TAPI-2, an inhibitor of ADAM17/TACE, significantly reduced both the activation of cathepsin D and the loss of ACE-2. Apoptosis of AECs induced by ER stress was measured by assays of mitochondrial function, JNK activation, caspase activation, and nuclear fragmentation. Apoptosis induced by either MG132 or the SP-C BRICHOS mutant G100S was significantly inhibited by the ANG receptor blocker saralasin and was completely abrogated by ANG1–7. Inhibition by ANG1–7 was blocked by the specific mas antagonist A779. These data show that ER stress-induced apoptosis is mediated by the autocrine ANGII/ANG1–7 system in human AECs and demonstrate effective blockade of SP-C mutation-induced apoptosis by ANG1–7. They also suggest that therapeutic strategies aimed at administering ANG1–7 or stimulating ACE-2 may hold potential for the management of ER stress-induced fibrotic lung disorders.

Cigarette Smoke-Induced Reduction of 14-3-3σ Expression Promotes The Progression of Non-Small Cell Lung Cancer

2021 ◽  
Author(s):  
Longxia Dai ◽  
Quanwen Deng ◽  
Aibin Liu ◽  
Shuya He ◽  
Qiong Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Small Cell Lung Cancer ◽  
Cigarette Smoke ◽  
Cell Lung Cancer ◽  
A549 Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Smoking Group ◽  
The Relationship

Abstract Background Lung cancer is a common malignant tumour and the leading cause of cancer death. Smoking is closely related to lung cancer, which can not only induce the occurrence of lung cancer but also affect its progress and prognosis. Objectives To investigated the relationship between smoking and 14-3-3σ protein expression in non-small-cell lung cancer (NSCLC), investigated the relationship between 14-3-3σ expression and cell migration in A549 cells induced by cigarette smoke extract (CSE) and explored whether DNA methylation plays a role in the decreased expression of 14-3-3σ induced by CSE. Methods 14-3-3σ protein expression was examined by immunohistochemistry in 152 NSCLC tissue samples. In vitro experiments were divided into three groups: The current smoking group (CS), the ex-smoking group (ES) and the normal control group (NC). Cell transfection was used for 14-3-3σ protein overexpression. The mRNA and protein expression levels of 14-3-3σ were detected by RT-PCR and Western blotting, respectively. Cell migration was detected by Transwell and wound-healing assays, and the methylation of 14-3-3σ was detected by methylation-specific PCR. Results 14-3-3σ protein expression was decreased in NSCLC patients with a history of smoking. The expression of 14-3-3σ was decreased in A549 cells treated with CSE. The migration capacity of A549 cells treated with CSE was enhanced. DNA methylation in the cigarette smoke-treated A549 cells was higher than that in the untreated cells. Conclusion Cigarette smoke induced reduction of 14-3-3σ expression can promote the progression of non-small cell lung cancer.

Role of DACH1 on proliferation, invasion, and apoptosis in human lung adenocarcinoma cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Junjie Yu ◽  
Ping Jiang ◽  
Ke Zhao ◽  
Zhiguo Chen ◽  
Tao Zuo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Tumor Cells ◽  
Human Lung ◽  
A549 Cells ◽  
Cancer Tissue ◽  
Lung Cancer Tissue ◽  
Adenocarcinoma Cells ◽  
Human Lung Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells

Objective: To investigate DACH1 protein expression in lung cancer tissue and matched paracancerous tissue, and explore its effect on proliferation, invasion, and apoptosis in human lung adenocarcinoma cells (HLACs). Methods: Tumor tissue and matched paracancerous tissue was collected from 46 patients with pathologically diagnosed lung cancer. RT-PCR was perfomed to detect DACH1 mRNA expression and immunohistochemistry to measured DACH1 protein expression. To determine the effect of DACH1 on lung cancer behavior, small interfering RNA (siRNA) was used to silence DACH1 expression in A549 cells. The impact on the proliferation of tumor cells was then observed by MTT assay, changes in the invasion of tumor cells were identified using transwell chamber assay, and the effects on apoptosis in the cell line were detected using flow cytometry. Results: The expression of DACH1 mRNA and DACH1 protein were significantly decreased in lung cancer tissue versus matched paracancerous control tissue. Silencing of DACH1 expression in A549 cells significantly enhanced cell proliferation, significantly increased cell invasion and significantly reduced spontaneous apoptosis. Conclusion: DACH1 is downregulated in lung adenocarcinoma tissue. In vitro assessment shows that DACH1 functions as a tumor suppressor, suggesting its potential use as new target for lung cancer treatment.

scholarly journals Idebenone has preventative and therapeutic effects on pulmonary fibrosis via preferential suppression of fibroblast activity

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Toshifumi Sugizaki ◽  
Ken-ichiro Tanaka ◽  
Teita Asano ◽  
Daisuke Kobayashi ◽  
Yuuki Hino ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Epithelial Cell Line ◽  
Therapeutic Effects ◽  
Synthetic Analogue ◽  
Apoptosis Resistance ◽  
Collagen Production ◽  
Alveolar Epithelial

AbstractAlveolar epithelial injury induced by reactive oxygen species (ROS) and abnormal collagen production by activated fibroblasts (myofibroblasts) is involved in the onset and exacerbation of idiopathic pulmonary fibrosis (IPF). Compared with alveolar epithelial cells, lung fibroblasts, especially myofibroblasts, exhibit an apoptosis-resistance phenotype (apoptosis paradox) that appears to be involved in IPF pathogenesis. Thus, we screened for chemicals eliciting preferential cytotoxicity of LL29 cells (lung fibroblasts from an IPF patient) compared with A549 cells (human lung alveolar epithelial cell line) from medicines already in clinical use. We identified idebenone, a synthetic analogue of coenzyme Q10 (CoQ10, an antioxidant) that has been used clinically as a brain metabolic stimulant. Idebenone induced cell growth inhibition and cell death in LL29 cells at a lower concentration than in A549 cells, a feature that was not observed for other antioxidant molecules (such as CoQ10) and two IPF drugs (pirfenidone and nintedanib). Administration of idebenone prevented bleomycin-induced pulmonary fibrosis and increased pulmonary ROS levels. Importantly, idebenone also improved pulmonary fibrosis and lung function when administered after the development of fibrosis, whereas administration of CoQ10 similarly prevented bleomycin-induced pulmonary fibrosis, but had no effect after its development. Administration of idebenone, but not CoQ10, suppressed bleomycin-induced increases in lung myofibroblasts. In vitro, treatment of LL29 cells with idebenone, but not CoQ10, suppressed TGF-β–induced collagen production. These results suggest that in addition to antioxidant activity, idebenone exerts inhibitory activity on the function of lung fibroblasts, with the former activity being preventative and the latter therapeutic for bleomycin-induced fibrosis. Thus, we propose that idebenone may be more therapeutically beneficial for IPF patients than current treatments.

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