scholarly journals A549 in-silico 1.0: A first computational model to simulate cell cycle dependent ion current modulation in the human lung adenocarcinoma

2021 ◽  
Vol 17 (6) ◽  
pp. e1009091
Author(s):  
Sonja Langthaler ◽  
Theresa Rienmüller ◽  
Susanne Scheruebel ◽  
Brigitte Pelzmann ◽  
Niroj Shrestha ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Membrane Potential ◽  
Lung Adenocarcinoma ◽  
Ion Channel ◽  
In Silico ◽  
Human Lung ◽  
Cell Model ◽  
Ion Current ◽  
Human Lung Adenocarcinoma

Lung cancer is still a leading cause of death worldwide. In recent years, knowledge has been obtained of the mechanisms modulating ion channel kinetics and thus of cell bioelectric properties, which is promising for oncological biomarkers and targets. The complex interplay of channel expression and its consequences on malignant processes, however, is still insufficiently understood. We here introduce the first approach of an in-silico whole-cell ion current model of a cancer cell, in particular of the A549 human lung adenocarcinoma, including the main functionally expressed ion channels in the plasma membrane as so far known. This hidden Markov-based model represents the electrophysiology behind proliferation of the A549 cell, describing its rhythmic oscillation of the membrane potential able to trigger the transition between cell cycle phases, and it predicts membrane potential changes over the cell cycle provoked by targeted ion channel modulation. This first A549 in-silico cell model opens up a deeper insight and understanding of possible ion channel interactions in tumor development and progression, and is a valuable tool for simulating altered ion channel function in lung cancer electrophysiology.

The ADAM17 protease promotes tobacco smoke carcinogen-induced lung tumorigenesis

2019 ◽  
Vol 41 (4) ◽  
pp. 527-538 ◽  
Author(s):  
Mohamed I Saad ◽  
Louise McLeod ◽  
Liang Yu ◽  
Hiromichi Ebi ◽  
Saleela Ruwanpura ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Tobacco Smoke ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Smoking History ◽  
Lung Carcinogenesis ◽  
Wild Type Littermate ◽  
Human Lung Adenocarcinoma ◽  
Erk Mapk

Abstract Lung cancer is the leading cause of cancer-related mortality, with most cases attributed to tobacco smoking, in which nicotine-derived nitrosamine ketone (NNK) is the most potent lung carcinogen. The ADAM17 protease is responsible for the ectodomain shedding of many pro-tumorigenic cytokines, growth factors and receptors, and therefore is an attractive target in cancer. However, the role of ADAM17 in promoting tobacco smoke carcinogen-induced lung carcinogenesis is unknown. The hypomorphic Adam17ex/ex mice—characterized by reduced global ADAM17 expression—were backcrossed onto the NNK-sensitive pseudo-A/J background. CRISPR-driven and inhibitor-based (GW280264X, and ADAM17 prodomain) ADAM17 targeting was employed in the human lung adenocarcinoma cell lines A549 and NCI-H23. Human lung cancer biopsies were also used for analyses. The Adam17ex/ex mice displayed marked protection against NNK-induced lung adenocarcinoma. Specifically, the number and size of lung lesions in NNK-treated pseudo-A/J Adam17ex/ex mice were significantly reduced compared with wild-type littermate controls. This was associated with lower proliferative index throughout the lung epithelium. ADAM17 targeting in A549 and NCI-H23 cells led to reduced proliferative and colony-forming capacities. Notably, among select ADAM17 substrates, ADAM17 deficiency abrogated shedding of the soluble IL-6 receptor (sIL-6R), which coincided with the blockade of sIL-6R-mediated trans-signaling via ERK MAPK cascade. Furthermore, NNK upregulated phosphorylation of p38 MAPK, whose pharmacological inhibition suppressed ADAM17 threonine phosphorylation. Importantly, ADAM17 threonine phosphorylation was significantly upregulated in human lung adenocarcinoma with smoking history compared with their cancer-free controls. Our study identifies the ADAM17/sIL-6R/ERK MAPK axis as a candidate therapeutic strategy against tobacco smoke-associated lung carcinogenesis.

scholarly journals Molecular Mechanisms Underlying Yatein-Induced Cell-Cycle Arrest and Microtubule Destabilization in Human Lung Adenocarcinoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1384 ◽  
Author(s):  
Shang-Tse Ho ◽  
Chi-Chen Lin ◽  
Yu-Tang Tung ◽  
Jyh-Horng Wu
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Lung Adenocarcinoma ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Human Lung ◽  
Microtubule Dynamics ◽  
Cycle Progression ◽  
Human Lung Adenocarcinoma

Yatein is an antitumor agent isolated from Calocedrus formosana Florin leaves extract. In our previous study, we found that yatein inhibited the growth of human lung adenocarcinoma A549 and CL1-5 cells by inducing intrinsic and extrinsic apoptotic pathways. To further uncover the effects and mechanisms of yatein-induced inhibition on A549 and CL1-5 cell growth, we evaluated yatein-mediated antitumor activity in vivo and the regulatory effects of yatein on cell-cycle progression and microtubule dynamics. Flow cytometry and western blotting revealed that yatein induces G2/M arrest in A549 and CL1-5 cells. Yatein also destabilized microtubules and interfered with microtubule dynamics in the two cell lines. Furthermore, we evaluated the antitumor activity of yatein in vivo using a xenograft mouse model and found that yatein treatment altered cyclin B/Cdc2 complex expression and significantly inhibited tumor growth. Taken together, our results suggested that yatein effectively inhibited the growth of A549 and CL1-5 cells possibly by disrupting cell-cycle progression and microtubule dynamics.

Identification and characterization of SP cells in human lung adenocarcinoma SPC-A1 cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22230-e22230
Author(s):  
Y. Zhu ◽  
L. Chen
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Serum Free ◽  
Human Lung Adenocarcinoma ◽  
Colony Forming Efficiency ◽  
Forming Efficiency ◽  
Human Lung Adenocarcinoma Cell

e22230 Background: There has been an increasing interest in recent years in the role stem cells play in health and disease. With an extensive understanding of their biology, a major role for stem cells in the malignant process has been proposed and the existence of cancer stem cells(CSCs) has been confirmed in hematopoietic malignancies, brain cancer, and solid organ malignancies including breast, prostate, colon, and pancreatic cancer. Lung cancer is the leading cause of cancer mortality in most large cities of China. It is possible that lung cancer contains cancer stem cells responsible for its malignancy. The aim of this study is to identify, characterize and enrich the CSC population that drives and maintains lung adenocarcinoma growth and metastasis. Methods: Side population (SP) cell analysis and sorting were applied to established human lung adenocarcinoma cell line and an attempt to further enrich them by preliminary serum-free culture before fluorescence activated cell sorting(FACS) was done. Stem cell properties of SP cells were evaluated by their proliferative index, colony-forming efficiency, tumorigenic potential, bi-differentiation capacity and the expression of common stem cell surface markers. Results: Lung cancer cells could grow in a serum-free Medium (SFM) as non-adherent spheres similar to neurospheres or mammospheres. The proportion of SP cells in cell spheres was significantly higher than that in cells grown as monolayers. SP cells had a greater proliferative index, a higher colony-forming efficiency and a greater ability to form tumor in vivo. SP cells were both CCA positive and SP-C positive while non-SP cells were only SP-C positive. Flow cytometric analysis of cell phenotyping showed that SP cells expressed CD133 and CD44, the common cell surface markers of cancer stem cells, while non-SP cells only expressed CD44. Conclusions: SP cells existed in human lung adenocarcinoma cell lines and they could be further enriched by preliminary serum-free culture before FACS sorting. SP cells possessed the properties of cancer stem cells. No significant financial relationships to disclose.

scholarly journals Transcriptional Response of Ovine Lung to Infection with Jaagsiekte Sheep Retrovirus

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Anna Eleonora Karagianni ◽  
Deepali Vasoya ◽  
Jeanie Finlayson ◽  
Henny M. Martineau ◽  
Ann R. Wood ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Animal Model ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Transcriptional Response ◽  
Human Lung Cancer ◽  
Ovine Pulmonary Adenocarcinoma ◽  
Jaagsiekte Sheep Retrovirus ◽  
Human Lung Adenocarcinoma ◽  
Naturally Occurring

ABSTRACT Jaagsiekte sheep retrovirus (JSRV) is the etiologic agent of ovine pulmonary adenocarcinoma (OPA), a neoplastic lung disease of sheep. OPA is an important economic and welfare issue for sheep farmers and a valuable naturally occurring animal model for human lung adenocarcinoma. Here, we used RNA sequencing to study the transcriptional response of ovine lung tissue to infection by JSRV. We identified 1,971 ovine genes differentially expressed in JSRV-infected lung compared to noninfected lung, including many genes with roles in carcinogenesis and immunomodulation. The differential expression of selected genes was confirmed using immunohistochemistry and reverse transcription-quantitative PCR. A key finding was the activation of anterior gradient 2, yes-associated protein 1, and amphiregulin in OPA tumor cells, indicating a role for this oncogenic pathway in OPA. In addition, there was differential expression of genes related to innate immunity, including genes encoding cytokines, chemokines, and complement system proteins. In contrast, there was little evidence for the upregulation of genes involved in T-cell immunity. Many genes related to macrophage function were also differentially expressed, reflecting the increased abundance of these cells in OPA-affected lung tissue. Comparison of the genes differentially regulated in OPA with the transcriptional changes occurring in human lung cancer revealed important similarities and differences between OPA and human lung adenocarcinoma. This study provides valuable new information on the pathogenesis of OPA and strengthens the use of this naturally occurring animal model for human lung adenocarcinoma. IMPORTANCE Ovine pulmonary adenocarcinoma is a chronic respiratory disease of sheep caused by jaagsiekte sheep retrovirus (JSRV). OPA is a significant economic problem for sheep farmers in many countries and is a valuable animal model for some forms of human lung cancer. Here, we examined the changes in host gene expression that occur in the lung in response to JSRV infection. We identified a large number of genes with altered expression in infected lung, including factors with roles in cancer and immune system function. We also compared the data from OPA to previously published data from human lung adenocarcinoma and found a large degree of overlap in the genes that were dysregulated. The results of this study provide exciting new avenues for future studies of OPA and may have comparative relevance for understanding human lung cancer.

scholarly journals Induction of Apoptosis and Cell Cycle Blockade by Helichrysetin in A549 Human Lung Adenocarcinoma Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Yen Fong Ho ◽  
Saiful Anuar Karsani ◽  
Wai Kuan Yong ◽  
Sri Nurestri Abd Malek
Keyword(s):  
Cell Cycle ◽  
Lung Adenocarcinoma ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cytotoxic Effect ◽  
Molecular Mechanisms ◽  
Human Lung ◽  
Cancer Cell Lines ◽  
Human Lung Adenocarcinoma ◽  
Induction Of Apoptosis

Researchers are looking into the potential development of natural compounds for anticancer therapy. Previous studies have postulated the cytotoxic effect of helichrysetin towards different cancer cell lines. In this study, we investigated the cytotoxic effect of helichrysetin, a naturally occurring chalcone on four selected cancer cell lines, A549, MCF-7, Ca Ski, and HT-29, and further elucidated its biochemical and molecular mechanisms in human lung adenocarcinoma, A549. Helichrysetin showed the highest cytotoxic activity against Ca Ski followed by A549. Changes in the nuclear morphology of A549 cells such as chromatin condensation and nuclear fragmentation were observed in cells treated with helichrysetin. Further evidence of apoptosis includes the externalization of phosphatidylserine and the collapse of mitochondrial membrane potential which are both early signs of apoptosis. These signs of apoptosis are related to cell cycle blockade at the S checkpoint which suggests that the alteration of the cell cycle contributes to the induction of apoptosis in A549. These results suggest that helichrysetin has great potentials for development as an anticancer agent.

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