scholarly journals Targeting Toll-like receptor 4 with CLI-095 (TAK-242) enhances the antimetastatic effect of the estrogen receptor antagonist fulvestrant on non-small cell lung cancer

2019 ◽  
Author(s):  
Sheng fan ◽  
Wenlin Qiu ◽  
Lequn Li ◽  
Dong Li ◽  
Yongde Liao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Metastatic Lymph Node ◽  
Small Cell ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Small Cell Lung ◽  
Toll Like Receptor 4 ◽  
Protein Levels ◽  
Antimetastatic Effect ◽  
Primary Nsclc

Abstract Background Estrogen plays a critical role in the invasiveness and metastasis of non-small cell lung cancer (NSCLC) through estrogen receptor β (ERβ). However, the antimetastatic effect of the ERβ antagonist fulvestrant was still limited in NSCLC patients in phase II clinical trials. Recently, Toll-like receptor 4 (TLR4) signaling was implicated in NSCLC metastasis. Our present study aimed to evaluate the synergistic antimetastatic effect of a combination of fulvestrant and the TLR4-specific inhibitor CLI-095 (TAK-242) on human NSCLC cells. Methods The expression levels of ERβ and TLR4 were detected by immunohistochemical (IHC) analysis of 180 primary NSCLC and 30 corresponding metastatic lymph node samples. The association between ERβ and TLR4 expression was analyzed. The aggressiveness of NSCLC cells treated with fulvestrant, CLI-095 or the drug combination and formation status of their invadopodia, invasion-associated structures, were investigated. The protein levels in NSCLC cells in different groups were determined by Western blot and immunofluorescence analyses. Results Here, a positive correlation between ERβ and TLR4 expression was observed in both primary NSCLC tissue (Spearman’s Rho correlation coefficient = 0.411, p<0.001) and metastatic lymph node tissue (Spearman’s Rho correlation coefficient = 0.374, p=0.009). The protein levels of ERβ in the A549 and H1793 cell lines induced by estrogen were decreased by fulvestrant, and this suppressive effect was significantly enhanced when fulvestrant was combined with CLI-095 (p<0.05 for both treatments). Both the migration and invasion of NSCLC cells were suppressed by fulvestrant or CLI-095 alone, and the combination of fulvestrant+CLI-095 showed the strongest inhibitory effect (p<0.05 for all treatments). In addition, the results demonstrated that CLI-095 also helped fulvestrant restrict the formation and function of invadopodia in NSCLC cells (p<0.05). Conclusions Collectively, our study results suggested that CLI-095 enhances the antimetastatic effect of fulvestrant on NSCLC and provided support for further investigation of the antitumor activity of combined therapy with antiestrogen and anti-TLR4 agents in the clinic.

scholarly journals Targeting Toll-like receptor 4 with CLI-095 (TAK-242) enhances the antimetastatic effect of the estrogen receptor antagonist fulvestrant on non-small cell lung cancer

2020 ◽  
Vol 22 (11) ◽  
pp. 2074-2086
Author(s):  
S. Fan ◽  
Y. Liao ◽  
W. Qiu ◽  
L. Li ◽  
D. Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Metastatic Lymph Node ◽  
Small Cell ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Small Cell Lung ◽  
Toll Like Receptor 4 ◽  
Protein Levels ◽  
Antimetastatic Effect ◽  
Primary Nsclc

Abstract Purpose Estrogen plays a critical role in the invasiveness and metastasis of non-small cell lung cancer (NSCLC) through estrogen receptor β (ERβ). However, the antimetastatic effect of the ERβ antagonist fulvestrant was still limited in NSCLC patients. Recently, Toll-like receptor 4 (TLR4) signaling was implicated in NSCLC metastasis. Our present study aimed to evaluate the synergistic antimetastatic effect of a combination of fulvestrant and the TLR4-specific inhibitor CLI-095 (TAK-242) on human NSCLC cells. Methods The expression levels of ERβ and TLR4 were detected by immunohistochemical (IHC) analysis of 180 primary NSCLC and 30 corresponding metastatic lymph node samples. The association between ERβ and TLR4 expression was analyzed. The aggressiveness of NSCLC cells treated with fulvestrant, CLI-095 or the drug combination and formation status of their invadopodia, invasion-associated structures, were investigated. The protein levels in NSCLC cells in different groups were determined by Western blot and immunofluorescence analyses. Results Here, a positive correlation between ERβ and TLR4 expression was observed in both primary NSCLC tissue (Spearman’s Rho correlation coefficient = 0.411, p < 0.001) and metastatic lymph node tissue (Spearman’s Rho correlation coefficient = 0.374, p = 0.009). The protein levels of ERβ in NSCLC cell lines were decreased by fulvestrant, and this suppressive effect was significantly enhanced when fulvestrant was combined with CLI-095 (p < 0.05). Both the migration and invasion of NSCLC cells were suppressed by fulvestrant or CLI-095 alone, and the combination of fulvestrant + CLI-095 showed the strongest inhibitory effect (p < 0.05). In addition, the results demonstrated that CLI-095 also helped fulvestrant restrict the formation and function of invadopodia in NSCLC cells (p < 0.05). Conclusions Collectively, our study results suggested that CLI-095 enhances the antimetastatic effect of fulvestrant on NSCLC and provided support for further investigation of the antitumor activity of combined therapy with antiestrogen and anti-TLR4 agents in the clinic.

scholarly journals Soluble Toll-like receptor 4 is a potential serum biomarker in non-small cell lung cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (26) ◽  
pp. 40106-40114 ◽  
Author(s):  
Feng Wei ◽  
Fan Yang ◽  
Jing Li ◽  
Yu Zheng ◽  
Wenwen Yu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Serum Biomarker ◽  
Toll Like Receptor ◽  
Small Cell Lung ◽  
Toll Like Receptor 4

scholarly journals Gram-Negative Pneumonia Augments Non–Small Cell Lung Cancer Metastasis through Host Toll-like Receptor 4 Activation

2019 ◽  
Vol 14 (12) ◽  
pp. 2097-2108 ◽  
Author(s):  
Stephen D. Gowing ◽  
Simon C. Chow ◽  
Jonathan J. Cools-Lartigue ◽  
Crystal B. Chen ◽  
Sara Najmeh ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cancer Metastasis ◽  
Small Cell ◽  
Toll Like Receptor ◽  
Small Cell Lung ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Lung Cancer Metastasis

scholarly journals Diethylstilbestrol, a Novel ANO1 Inhibitor, Exerts an Anticancer Effect on Non-Small Cell Lung Cancer via Inhibition of ANO1

2021 ◽  
Vol 22 (13) ◽  
pp. 7100
Author(s):  
Yohan Seo ◽  
Sung Baek Jeong ◽  
Joo Han Woo ◽  
Oh-Bin Kwon ◽  
Sion Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
High Throughput Screening ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Small Cell ◽  
Channel Activity ◽  
Small Cell Lung ◽  
Protein Levels

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality; thus, therapeutic targets continue to be developed. Anoctamin1 (ANO1), a novel drug target considered for the treatment of NSCLC, is a Ca2+-activated chloride channel (CaCC) overexpressed in various carcinomas. It plays an important role in the development of cancer; however, the role of ANO1 in NSCLC is unclear. In this study, diethylstilbestrol (DES) was identified as a selective ANO1 inhibitor using high-throughput screening. We found that DES inhibited yellow fluorescent protein (YFP) fluorescence reduction caused by ANO1 activation but did not inhibit cystic fibrosis transmembrane conductance regulator channel activity or P2Y activation-related cytosolic Ca2+ levels. Additionally, electrophysiological analyses showed that DES significantly reduced ANO1 channel activity, but it more potently reduced ANO1 protein levels. DES also inhibited the viability and migration of PC9 cells via the reduction in ANO1, phospho-ERK1/2, and phospho-EGFR levels. Moreover, DES induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage in PC9 cells, but it did not affect the viability of hepatocytes. These results suggest that ANO1 is a crucial target in the treatment of NSCLC, and DES may be developed as a potential anti-NSCLC therapeutic agent.

scholarly journals Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Katrina Kildey ◽  
Neha S. Gandhi ◽  
Katherine B. Sahin ◽  
Esha T. Shah ◽  
Eric Boittier ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genome Instability ◽  
Small Cell ◽  
Small Cell Lung ◽  
Protein Levels ◽  
Platinum Based Chemotherapy ◽  
Platinum Agents

AbstractPlatinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell division cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. We demonstrate that in patients and in vitro analyses, CDCA3 levels correlate with measures of genome instability and platinum sensitivity, whereby CDCA3high tumours are sensitive to cisplatin and carboplatin. In NSCLC, CDCA3 protein levels are regulated by the ubiquitin ligase APC/C and cofactor Cdh1. Here, we identified that the degradation of CDCA3 is modulated by activity of casein kinase 2 (CK2) which promotes an interaction between CDCA3 and Cdh1. Supporting this, pharmacological inhibition of CK2 with CX-4945 disrupts CDCA3 degradation, elevating CDCA3 levels and increasing sensitivity to platinum agents. We propose that combining CK2 inhibitors with platinum-based chemotherapy could enhance platinum efficacy in CDCA3low NSCLC tumours and benefit patients.

scholarly journals Plasma Proteomic Analysis in Non-Small Cell Lung Cancer Patients Treated with PD-1/PD-L1 Blockade

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3116
Author(s):  
Mohamed Eltahir ◽  
Johan Isaksson ◽  
Johanna Sofia Margareta Mattsson ◽  
Klas Kärre ◽  
Johan Botling ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cluster Analysis ◽  
Small Cell Lung Cancer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Response Prediction ◽  
Small Cell ◽  
Small Cell Lung ◽  
Activation Markers ◽  
Protein Levels

Checkpoint inhibitors have been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only biomarker measure routinely used to select patients for immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1 therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related proteins. The plasma protein levels were associated with clinical and histopathological parameters, as well as therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct protein profiles associated with high and low immune protein levels, designated as “hot” and “cold”. Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than tumor PD-L1 expression or each protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified protein signatures that could predict the response to anti-PD-(L)1 therapy.

scholarly journals LncRNA MCM3AP-AS1 sponges miR-148a to enhance cell invasion and migration in small cell lung cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hua Luo ◽  
Yukun Zhang ◽  
Guangmei Qin ◽  
Bing Jiang ◽  
Lili Miao
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cell Invasion ◽  
Small Cell ◽  
Small Cell Lung ◽  
Invasion And Migration ◽  
Protein Levels ◽  
Underlying Mechanisms ◽  
And Migration

Abstract Background MCM3AP-AS1 is a recently characterized lncRNA playing an oncogenic role in several cancers. However, its role in lung cancer remains unknown. Here, we aimed to explore the functions of MCM3AP-AS1 in small cell lung cancer (SCLC) and the possible underlying mechanisms. Methods MCM3AP-AS1 and ROCK1 levels in SCLC patients were analyzed by qPCR. RNA pull-down and luciferase assays were performed to analyze the interaction between MCM3AP-AS1 and miR-148a. ROCK1 mRNA and protein levels were detected by qPCR and Western blot, respectively. Cell invasion and migration were analyzed by Transwell assays. Results MCM3AP-AS1 was upregulated in patients with SCLC, and a high MCM3AP-AS1 level was accompanied by a low survival rate. The binding of MCM3AP-AS1 to miR-148a predicted by bioinformatics analysis was verified by RNA pull-down and luciferase assays. However, MCM3AP-AS1 and miR-148a did not affect each other’s expression. ROCK1 was upregulated in SCLC tissues and positively correlated with MCM3AP-AS1. In SCLC cells, MCM3AP-AS1 overexpression increased ROCK1 and promoted cancer cell invasion and migration, while miR-148a overexpression showed the opposite effects and attenuated the effects of MCM3AP-AS1 overexpression on ROCK1 expression and cell behaviors. Conclusions MCM3AP-AS1 sponges miR-148a, thereby increasing SCLC cell invasion and migration via upregulating ROCK1 expression.

Cytogenetic Findings in Primary Non-Small Cell Lung Cancer

1994 ◽  
Vol 80 (2) ◽  
pp. 151-156
Author(s):  
Elvira D'Alessandro ◽  
Maria Luisa Lo Re ◽  
Roberto Crisci ◽  
Claudio Ligas ◽  
Giorgio Furio Coloni
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Chromosome Loss ◽  
Small Cell Lung ◽  
Primary Nsclc ◽  
Cytogenetic Analyses ◽  
Triploid Clone

Non-small cell lung cancer (NSCLC) shows a complex cytogenetic heterogeneity and up to now no particular chromosomal aberration seems to characterize its malignant evolution. We therefore performed cytogenetic analyses of 20 primary NSCLC, 8 adenocarcinomas and 12 squamous cell carcinomas on direct preparations or short-term cultures. Only 1 case was analyzed after long-term culture. Results were obtained from 11 samples and clonal rearrangements were found in 3 cases, a diploid and a near-triploid clone with several aberrations such as i (9q), rob (14; 15) and rob (21; 21) in 1 case, a near-triploid clone in 1 case, and Y chromosome loss in 1 case. Other aberrations found were sporadic, but + 7 aneuploidy and translocations involving 1p were detected in 2 and 3 samples respectively. Although to date it has been very difficult to recognize primary changes in NSCLC, nevertheless a literature review and our results indicate that i(9q) and robertsonian translocations are relevant findings.

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