scholarly journals The Sulfotransferase SULT1C2 Is Epigenetically Activated and Transcriptionally Induced by Tobacco Exposure and Is Associated with Patient Outcome in Lung Adenocarcinoma

2021 ◽  
Vol 19 (1) ◽  
pp. 416
Author(s):  
Candace Johnson ◽  
Daniel J. Mullen ◽  
Suhaida A. Selamat ◽  
Mihaela Campan ◽  
Ite A. Offringa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Methylation ◽  
Lung Adenocarcinoma ◽  
Binding Site ◽  
Cell Line ◽  
Cigarette Smoke ◽  
Cell Lines ◽  
Normal Lung ◽  
Tobacco Exposure

Lung cancer is the leading cause of cancer-related death. Tobacco exposure is associated with 80–90% of lung cancer cases. The SULT1C2 sulfotransferase modifies xenobiotic compounds to enhance secretion but can also render these compounds carcinogenic. To determine if SULT1C2 contributes to tobacco-related carcinogenesis in the lung, we analyzed the expression and epigenetic state of SULT1C2 in human lung adenocarcinoma (LUAD) samples and in LUAD cell lines exposed to cigarette smoke condensate (CSC). SULT1C2 expression was significantly positively correlated to overall LUAD patient survival in smokers, was elevated in LUAD tumors compared to adjacent non-tumor lung, and was significantly correlated with levels of patient exposure to tobacco smoke. SULT1C2 promoter DNA methylation was inversely correlated with expression in LUAD, and hypomethylation of the SULT1C2 promoter was observed in Asian patients, as compared to Caucasians. In vitro analysis of LUAD cell lines indicates that CSC stimulates expression of SULT1C2 in a dose-dependent and cell-line-specific manner. In vitro methylation of the SULT1C2 promoter significantly decreased transcriptional activity of a reporter plasmid, and SULT1C2 expression was activated by the DNA demethylating agent 5-Aza-2′-deoxycytidine in a cell line in which the SULT1C2 promoter was hypermethylated. An aryl hydrocarbon receptor (AHR) binding site was detected spanning critical methylation sites upstream of SULT1C2. CSC exposure significantly increased AHR binding to this predicted binding site in the SULT1C2 promoter in multiple lung cell lines. Our data suggest that CSC exposure leads to activation of the AHR transcription factor, increased binding to the SULT1C2 promoter, and upregulation of SULT1C2 expression and that this process is inhibited by DNA methylation at the SULT1C2 locus. Additionally, our results suggest that the level of SULT1C2 promoter methylation and gene expression in normal lung varies depending on the race of the patient, which could in part reflect the molecular mechanisms of racial disparities seen in lung cellular responses to cigarette smoke exposure.

scholarly journals The Sulfotransferase SULT1C2 is Epigenetically Activated and Transcriptionally Induced by Tobacco Exposure and is Associated with Patient Outcome in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Candace Johnson ◽  
Daniel J. Mullen ◽  
Suhaida A. Selamat ◽  
Mihaela Campan ◽  
Ite A. Offringa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Methylation ◽  
Lung Adenocarcinoma ◽  
Binding Site ◽  
Cell Line ◽  
Cigarette Smoke ◽  
Cell Lines ◽  
Normal Lung ◽  
Tobacco Exposure

Abstract Lung cancer is the leading cause of cancer-related death. Tobacco exposure is associated with 80–90% of lung cancer cases. The SULT1C2 sulfotransferase modifies xenobiotic compounds to enhance secretion but can also render these compounds carcinogenic. To determine if SULT1C2 contributes to tobacco-related carcinogenesis in the lung, we analyzed the expression and epigenetic state of SULT1C2 in human patients in relation to smoking history as well as lung adenocarcinoma (LUAD) cell lines exposed to cigarette smoke condensate (CSC). SULT1C2 expression was significantly positively correlated to overall LUAD patient survival in smokers, was elevated in LUAD tumors, and was significantly correlated with levels of patient exposure to tobacco smoke. SULT1C2 promoter DNA methylation was inversely correlated with expression in LUAD and hypomethylation of the SULT1C2 promoter was observed in Asian patients, as compared to Caucasians. In vitro analysis of LUAD cell lines indicates that CSC stimulates expression of SULT1C2 in a dose-dependent and cell-line specific manner. In vitro methylation of the SULT1C2 promoter significantly decreased transcriptional activity or a reporter plasmid and SULT1C2 expression was activated by the DNA demethylating agent 5-Aza-2’-deoxycytidine in a cell line in which the SULT1C2 promoter was hypermethylated. An aryl hydrocarbon receptor (AHR) binding site was detected spanning critical methylation sites upstream of SULT1C2. CSC exposure significantly increased AHR binding to this predicted binding site in the SULT1C2 promoter in multiple lung cell lines. Our data suggests that CSC exposure leads to activation of the AHR transcription factor, increased binding to the SULT1C2 promoter, and upregulation of SULT1C2 expression, and that this process is inhibited by DNA methylation at the SULT1C2 locus. Additionally, our results suggest that the level of SULT1C2 promoter methylation and gene expression in normal lung varies depending on the race of the patient, which could in part reflect the molecular mechanisms of racial disparities seen in lung cellular responses to cigarette smoke exposure.

scholarly journals Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
He Du ◽  
Bi Chen ◽  
Nan-Lin Jiao ◽  
Yan-Hua Liu ◽  
San-Yuan Sun ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Glutathione Peroxidase ◽  
Lung Adenocarcinoma ◽  
Cell Line ◽  
A549 Cells ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Normal Lung

The aim of this study was to explore the roles of GPX2, a member of the glutathione peroxidase family (GPXs, GSH-Px), in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). GPX2 was found to be the most significantly upregulated gene in a DDP-resistant A549/DDP cell line compared with the parental A549 cell line by RNA sequencing. The knockdown of GPX2 expression in A549/DDP cells inhibited cell proliferation in vitro and in vivo, decreased the IC50 values of DDP, induced apoptosis, inhibited the activities of GSH-Px and superoxide dismutase (SOD), inhibited ATP production and glucose uptake, and increased malondialdehyde (MDA) and reactive oxygen species (ROS) production; while GPX2 overexpression in A549 cells resulted in the opposite effects. Using gene set enrichment analysis (GSEA), we found that GPX2 may be involved in DDP resistance through mediating drug metabolism, the cell cycle, DNA repair and energy metabolism, and the regulation of an ATP-binding cassette (ABC) transporters member ABCB6, which is one of the hallmark genes in glycolysis. Moreover, immunohistochemistry revealed that GPX2 was upregulated in 58.6% (89/152) of LUAD cases, and elevated GPX2 expression was correlated with high expression of ABCB6, high 18-fluorodeoxyglucose (18F-FDG) uptake, and adverse disease-free survival (DFS) in our cohort. The Cancer Genome Atlas (TCGA) data also indicated that GPX2 expression was higher in LUAD than it was in normal lung tissues, and the mRNA expression levels of GPX2 and ABCB6 were positively correlated. In conclusion, our study demonstrates that GPX2 acts as oncogene in LUAD and promotes DDP resistance by regulating oxidative stress and energy metabolism.

scholarly journals Recombinant human interleukin-4 inhibits growth of some human lung tumor cell lines in vitro and in vivo

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2837-2844 ◽  
Author(s):  
MS Topp ◽  
M Koenigsmann ◽  
A Mire-Sluis ◽  
D Oberberg ◽  
F Eitelbach ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Lung Cancer Cell ◽  
Small Cell Lung

Abstract Cytokines play an important role in activating the immune system against malignant cells. One of these cytokines, interleukin-4 (IL-4) has entered clinical phase I trials because of its immunoregulatory potency. In the present study we report that recombinant human (rh) IL- 4 has major direct antiproliferative effects on one human lung cancer cell line (CCL 185) in vitro as measured by a human tumor cloning assay (HTCA), tritiated thymidine uptake, and counting cell numbers and marginal activity in a second cell line (HTB 56) in the HTCA. This activity could be abolished by neutralizing antibody against rhIL-4. The biological response of the tumor cells to the cytokine is correlated with expression of receptors for human IL-4 on both the mRNA level and the protein level. The responsive cell line, CCL 185, secretes IL-6 after being incubated with rhIL-4. On the other hand, neutralizing antibodies against IL-6 showed no influence on the growth modulatory efficacy of rhIL-4 in this cell line. Furthermore, CCL 185 does not show detectable production of IL-1, tumor necrosis factor alpha or interferon gamma after incubation with rhIL-4. Thus, the response to rhIL-4 is not mediated through autocrine production of these cytokines triggered by rhIL-4. In a next series of experiments some of the cell lines were xenotransplanted to BALB/c nu/nu mice. Subsequently, the mice were treated for 12 days with two doses of 0.5 mg/m2 rhIL-4 or control vehicle subcutaneously per day. Treatment with rhIL-4 yielded a significant inhibition of tumor growth versus control in two of the non-small cell lung cancer cell lines being responsive in vitro (CCL 185, HTB 56). Histology of the tumors in both groups showed no marked infiltration of the tumors with murine hematopoietic and lymphocytic cells consistent with the species specificity of IL-4. In contrast, no tumor growth inhibition was found in the small cell lung cancer cell lines (HTB 119, HTB 120) being nonresponsive in vitro. We conclude that rhIL-4 has direct antiproliferative effects on the growth of some human non-small cell lung cancer cell lines in vitro and in vivo, which together with its regulatory effects on various effector cell populations makes this cytokine an interesting candidate for further investigation in experimental cancer treatment.

scholarly journals KRT6A Promotes EMT and Cancer Stem Cell Transformation in Lung Adenocarcinoma

2020 ◽  
Vol 19 ◽  
pp. 153303382092124
Author(s):  
Bin Yang ◽  
Wei Zhang ◽  
Mengmeng Zhang ◽  
Xuhong Wang ◽  
Shengzu Peng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Lung Adenocarcinoma ◽  
Biological Function ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Normal Lung ◽  
Mesenchymal Transition

Aim: Keratin 6A is a type II cytokeratin which is important in forming nail bed, filiform papillae, the epithelial lining of oral mucosa, and esophagus; recently, keratin 6A was found hyperexpressed in different types of cancer. But, the biological function of keratin 6A in lung adenocarcinoma still remains unclear. Therefore, in current study, we investigated the biological role of keratin 6A in lung adenocarcinoma. Methods: By utilizing The Cancer Genome Atlas database, we investigated the expression profile of keratin 6A and its relationship with other clinical parameters in lung adenocarcinoma. The biological function of keratin 6A in lung adenocarcinoma was also investigated by using A549 and PC-9 lung cancer cell lines in vitro. Results: Our data indicate that, compared with normal lung tissue samples, keratin 6A was hyperexpressed in lung adenocarcinoma. Moreover, keratin 6A hyperexpression was positively correlated with lymph node positive and aggressive tumor T stage. Keratin 6A knockdown inhibited the cell proliferation, migration, and colony formation ability but not cell death in lung adenocarcinoma cells. In addition, we found keratin 6A exerted its phenotype via promoting cancer stem cells (CXCR4high/CD133high) transformation and epithelial–mesenchymal transition. Conclusion: In conclusion, current study suggests that hyperexpressed keratin 6A in lung adenocarcinoma promotes lung cancer proliferation and metastasis via epithelial–mesenchymal transition and cancer stem cells transformation.

scholarly journals Heterogeneous Off-Target Effects of Ultra-Low Dose Dimethyl Sulfoxide (DMSO) on Targetable Signaling Events in Lung Cancer In Vitro Models

2021 ◽  
Vol 22 (6) ◽  
pp. 2819
Author(s):  
Elisa Baldelli ◽  
Mahalakshmi Subramanian ◽  
Abduljalil M. Alsubaie ◽  
Guy Oldaker ◽  
Maria Emelianenko ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dimethyl Sulfoxide ◽  
Cell Line ◽  
Cell Lines ◽  
Drug Screening ◽  
Drug Targets ◽  
Clinical Testing ◽  
In Vitro Drug Screening ◽  
Target Effects

Targetable alterations in cancer offer novel opportunities to the drug discovery process. However, pre-clinical testing often requires solubilization of these drugs in cosolvents like dimethyl sulfoxide (DMSO). Using a panel of cell lines commonly used for in vitro drug screening and pre-clinical testing, we explored the DMSO off-target effects on functional signaling networks, drug targets, and downstream substrates. Eight Non-Small Cell Lung Cancer (NSCLC) cell lines were incubated with three concentrations of DMSO (0.0008%, 0.002%, and 0.004% v/v) over time. Expression and activation levels of 187 proteins, of which 137 were kinases and downstream substrates, were captured using the Reverse Phase Protein Array (RPPA). The DMSO effect was heterogeneous across cell lines and varied based on concentration, exposure time, and cell line. Of the 187 proteins measured, all were statistically different in at least one comparison at the highest DMSO concentration, followed by 99.5% and 98.9% at lower concentrations. Only 46% of the proteins were found to be statistically different in more than 5 cell lines, indicating heterogeneous response across models. These cell line specific alterations modulate response to in vitro drug screening. Ultra-low DMSO concentrations have broad and heterogeneous effects on targetable signaling proteins. Off-target effects need to be carefully evaluated in pre-clinical drug screening and testing.

scholarly journals Upregulation of long intergenic noncoding RNA LINC00092 indicates favorable survival in lung adenocarcinoma via tumor growth inhibition

2019 ◽  
Author(s):  
Mingyan Jiang ◽  
Ke Wang ◽  
Ziwen Zhao ◽  
Yujun Li ◽  
Hua He ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Lung Adenocarcinoma ◽  
Noncoding Rna ◽  
Lung Squamous Cell Carcinoma ◽  
Molecular Therapy ◽  
Normal Lung ◽  
Cox Regression Analysis ◽  
Long Intergenic Noncoding Rna

Abstract Background Long intergenic noncoding RNA 00092 (LINC00092) is a recently identified novel RNA that acts on cancer-associated fibroblasts (CAFs) to drive the progression of ovarian cancer. Because CAFs also play a vital role in lung cancer, we hypothesized that LINC00092 is associated with lung cancer.Methods The expression level of LINC00092 was examined in 93 cases of non-small cell lung cancer (NSCLC) tumor tissues and adjacent normal lung tissues, and its clinical effect on prognosis was evaluated using the Kaplan-Meier method, log-rank test and Cox regression analysis based on The Cancer Genome Atlas (TCGA) data. The effect of LINC00092 on tumor growth was further assessed in vitro .Results LINC00092 was significantly downregulated in 76.3% (71/93) of lung cancer tissues compared to that in their normal counterparts ( P < 0.001), and high expression of LINC00092 led to a better prognosis with increased survival time (1632 days vs. 1171 days; P = 0.087) and decreased mortality (hazard rate, HR = 0.73, 95%CI = 0.51-1.05) than low expression in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma (LSCC) patients. Additionally, upregulation of LINC00092 inhibited LUAD cell proliferation and tumorigenic ability in vitro .Conclusions LINC00092 is an indicator of favorable LUAD prognosis. Targeted molecular therapy directed at LINC00092 upregulation may be a valuable strategy to fight LUAD.

scholarly journals Recombinant human interleukin-4 inhibits growth of some human lung tumor cell lines in vitro and in vivo

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2837-2844
Author(s):  
MS Topp ◽  
M Koenigsmann ◽  
A Mire-Sluis ◽  
D Oberberg ◽  
F Eitelbach ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Lung Cancer Cell ◽  
Small Cell Lung

Cytokines play an important role in activating the immune system against malignant cells. One of these cytokines, interleukin-4 (IL-4) has entered clinical phase I trials because of its immunoregulatory potency. In the present study we report that recombinant human (rh) IL- 4 has major direct antiproliferative effects on one human lung cancer cell line (CCL 185) in vitro as measured by a human tumor cloning assay (HTCA), tritiated thymidine uptake, and counting cell numbers and marginal activity in a second cell line (HTB 56) in the HTCA. This activity could be abolished by neutralizing antibody against rhIL-4. The biological response of the tumor cells to the cytokine is correlated with expression of receptors for human IL-4 on both the mRNA level and the protein level. The responsive cell line, CCL 185, secretes IL-6 after being incubated with rhIL-4. On the other hand, neutralizing antibodies against IL-6 showed no influence on the growth modulatory efficacy of rhIL-4 in this cell line. Furthermore, CCL 185 does not show detectable production of IL-1, tumor necrosis factor alpha or interferon gamma after incubation with rhIL-4. Thus, the response to rhIL-4 is not mediated through autocrine production of these cytokines triggered by rhIL-4. In a next series of experiments some of the cell lines were xenotransplanted to BALB/c nu/nu mice. Subsequently, the mice were treated for 12 days with two doses of 0.5 mg/m2 rhIL-4 or control vehicle subcutaneously per day. Treatment with rhIL-4 yielded a significant inhibition of tumor growth versus control in two of the non-small cell lung cancer cell lines being responsive in vitro (CCL 185, HTB 56). Histology of the tumors in both groups showed no marked infiltration of the tumors with murine hematopoietic and lymphocytic cells consistent with the species specificity of IL-4. In contrast, no tumor growth inhibition was found in the small cell lung cancer cell lines (HTB 119, HTB 120) being nonresponsive in vitro. We conclude that rhIL-4 has direct antiproliferative effects on the growth of some human non-small cell lung cancer cell lines in vitro and in vivo, which together with its regulatory effects on various effector cell populations makes this cytokine an interesting candidate for further investigation in experimental cancer treatment.

scholarly journals In vitro cytotoxic and genotoxic effects of donkey milk on lung cancer and normal cells lines

2019 ◽  
Vol 37 (No. 1) ◽  
pp. 29-35 ◽  
Author(s):  
Cetin Akca ◽  
Ozgur Vatan ◽  
Dilek Yilmaz ◽  
Huzeyfe HURIYET ◽  
Nilüfer Cinkilic ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Micronucleus Test ◽  
A549 Cells ◽  
Tumor Cell Line ◽  
Normal Lung ◽  
Dna Breaks ◽  
Donkey Milk ◽  
Genotoxic Effects

In vitro cytotoxic and genotoxic effects of donkey milk on cancer (A549) and normal (BEAS-2B) lung cell lines were investigated. The XTT and WST-1 tests as well as clonogenic assays were used to evaluate cytotoxicity. The comet assay and micronucleus test were used as genotoxicity endpoints. Donkey milk showed lower cytotoxic effects against normal lung cell line BEAS-2B in comparison to the tumor cell line A549. Genotoxicity experiments revealed dose dependent increases in the frequencies of micronuclei and single stranded DNA breaks in A549 cells whereas no significant damage was observed in BEAS-2B cells. The results indicate that donkey milk has anti-proliferative and genotoxic effects on lung cancer cells at concentrations which are non-toxic to normal lung cells.

scholarly journals In vitro Cytotoxic Activity of Sesamin Isolated from Vismia baccifera var. dealbata Triana & Planch (Guttiferae) Collected from Venezuela

2008 ◽  
Vol 3 (10) ◽  
pp. 1934578X0800301 ◽  
Author(s):  
Fabiola Salas ◽  
Janne Rojas ◽  
Antonio Morales ◽  
Maria E. Ramos-Nino ◽  
Nelida G. Colmenares
Keyword(s):  
Lung Cancer ◽  
Cytotoxic Activity ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Cytostatic Activity ◽  
Lung Cancer Cell

Sesamin extracted from Vismia baccifera var. dealbata was demonstrated to have cytostatic activity on the cancer cell lines tested, particularly the lung cancer cell line, with an IC50 of 1 g/L.

The therapeutic effects of vitamin C on lung cancer cells.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18523-e18523
Author(s):  
Ashorne Krithiesh Mahenthiran ◽  
Gurusingham Sitta Sittampalam ◽  
Raj Somasundaram ◽  
Sanjit Nirmalanandhan
Keyword(s):  
Lung Cancer ◽  
Vitamin C ◽  
Cancer Cells ◽  
Cell Lines ◽  
In Vitro Study ◽  
Lung Cancer Cells ◽  
Normal Lung ◽  
Lung Cells ◽  
Experimental Conditions

e18523 Background: In this in-vitro study, we determined the effects of vitamin C (Ascorbic acid), an essential vitamin, on two different lung cancer cell lines (H358 – Bronchioalveolar Carcinoma and A549 – Epithelial Lung carcinoma) and two normal lung cell lines as control groups (MRC5 – Human lung fibroblast tissue and NL20 – Lung epithelial cells). Methods: In the study, the four cell lines were treated with Vitamin C starting from 0.005 molar concentrations and serially diluted down 1:3 ratios to low nM concentrations. All experiments were carried out in a period of 4 weeks. The viability of the cell lines after the drug treatment was measured using a MTS cell proliferation assay. Results: The study was inconclusive since the viability of both normal and lung cells were equally affected under the experimental conditions except that the dosage of vitamin C that killed 50% of H358 was at a slightly lower concentration than the dosage of vitamin C that killed 50% of the normal lung cells. These results show that there is a possibility of an optimal dosage that will only harm cancerous cells in specific cancers and not on all cancers. Conclusions: These results were inconclusive; probably due to the fact that experimental conditions in this in-vitro study may not be appropriate to show the effects of Vitamin C on lung cancer cells. It is possible that lower dosages of vitamin C may still kill cancer cells selectively, and may also be more effective in cancers in ther tissues. Despite these drawbacks, in-vivo experiments in animal models with lung cancer may show the benefits of Vitamin C in combination with standard of care cancer drugs. Future experiments will examine combinations experiments in vitro and in animals to study the beneficial effects of Vitamin C.

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