scholarly journals Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis

2020 ◽  
Author(s):  
Xu Feng ◽  
En-Shi Xu
Keyword(s):  
Lung Cancer ◽  
Matrix Metalloproteinases ◽  
Brain Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Anaplastic Lymphoma ◽  
And Migration

Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial–mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose dependent or time dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function via the downregulation of MMPs and EMT in NSCLC metastasis.

scholarly journals Baicalin Inhibits EMT through PDK1/AKT Signaling in Human Nonsmall Cell Lung Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jia Chen ◽  
Cheng-Bo Yuan ◽  
Bo Yang ◽  
Xuan Zhou
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Cell Lung Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Nonsmall Cell Lung Cancer ◽  
Dependent Manner ◽  
Migration Ability ◽  
Mesenchymal Transition ◽  
And Migration ◽  
Human Nsclc

Background. Baicalin is a naturally occurring compound with anticancer, antioxidant, and anti-inflammatory properties. However, the mechanism underlying its anticancer activity on nonsmall cell lung cancer (NSCLC) remains unclear. Methods. The effects of baicalin on the progression and metastasis of experimental NSCLC cell lines were studied in vitro and in vivo. Wound-healing and transwell assays were performed to evaluate the potency of baicalin and the motility and migration ability of NCI-H460 cells. Immunofluorescence assay, western blot assay, and immunohistochemistry test were conducted to investigate the inhibiting effect of baicalin on the epithelial-mesenchymal transition (EMT) of NSCLC. Results. Baicalin inhibited the proliferation and migration of NCI-H446 human NSCLC cells in a dose-dependent manner, reduced the expression levels of phospho-3-phosphoinositide-dependent protein kinase 1 (p-PDK1) and phosphor-serine/threonine-protein kinase (p-AKT), reversed the levels of EMT markers, and inhibited the migration of NSCLC cells. Conclusions. Baicalin impedes EMT by inhibiting the PDK1/AKT pathway in human NSCLC and thus may be an effective alternative treatment for carcinoma and a new candidate antimetastasis drug.

scholarly journals Norcycloartocarpin targets Akt and suppresses Akt-dependent survival and epithelial-mesenchymal transition in lung cancer cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0254929
Author(s):  
Nongyao Nonpanya ◽  
Kittipong Sanookpan ◽  
Keerati Joyjamras ◽  
Duangdao Wichadakul ◽  
Boonchoo Sritularak ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Dermal Papilla ◽  
Human Lung Cancer ◽  
Dependent Manner ◽  
Dermal Papilla Cells ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Dose Dependent

In searching for novel targeted therapeutic agents for lung cancer treatment, norcycloartocarpin from Artocarpus gomezianus was reported in this study to promisingly interacted with Akt and exerted the apoptosis induction and epithelial-to-mesenchymal transition suppression. Selective cytotoxic profile of norcycloartocarpin was evidenced with approximately 2-fold higher IC50 in normal dermal papilla cells (DPCs) compared with human lung cancer A549, H460, H23, and H292 cells. We found that norcycloartocarpin suppressed anchorage-independent growth, cell migration, invasion, filopodia formation, and decreased EMT in a dose-dependent manner at 24 h, which were correlated with reduced protein levels of N-cadherin, Vimentin, Slug, p-FAK, p-Akt, as well as Cdc42. In addition, norcycloartocarpin activated apoptosis caspase cascade associating with restoration of p53, down-regulated Bcl-2 and augmented Bax in A549 and H460 cells. Interestingly, norcycloartocarpin showed potential inhibitory role on protein kinase B (Akt) the up-stream dominant molecule controlling EMT and apoptosis. Computational molecular docking analysis further confirmed that norcycloartocarpin has the best binding affinity of -12.52 kcal/mol with Akt protein at its critical active site. As Akt has recently recognized as an attractive molecular target for therapeutic approaches, these findings support its use as a plant-derived anticancer agent in cancer therapy.

scholarly journals Benzotriazole Enhances Cell Invasive Potency in Endometrial Carcinoma Through CTBP1-Mediated Epithelial-Mesenchymal Transition

2017 ◽  
Vol 44 (6) ◽  
pp. 2357-2367 ◽  
Author(s):  
Yiquan Wang ◽  
Chencheng Dai ◽  
Cheng Zhou ◽  
Wenqu Li ◽  
Yujia Qian ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Expression Patterns ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
Female Reproductive Health ◽  
Gene Microarray Analysis ◽  
And Migration

Background/Aims: Benzotriazole (BTR) and its derivatives, such as intermediates and UV stabilizers, are important man-made organic chemicals found in everyday life that have been recently identified as environmental toxins and a threat to female reproductive health. Previous studies have shown that BTR could act as a carcinogen by mimicking estrogen. Environmental estrogen mimics could promote the initiation and development of female cancers, such as endometrial carcinoma, a type of estrogenic-sensitive malignancy. However, there is little information on the relationship between BTR and endometrial carcinoma. In this study, we aimed to demonstrate the biological function of BTR in endometrial carcinoma and explored the underlying mechanism. Methods: The CCK-8 assay was performed to detect cell viability; transwell-filter assay was used to assess cell invasion; gene microarray analysis was employed to determine gene expression patterns in response to BTR treatment; western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were carried out to detect the expression levels of BTR-related genes. Results: Our data showed that BTR could induce the invasion and migration of endometrial carcinoma cells (Ishikawa and HEC-1-B). In addition, BTR increased the expression level of CTBP1, which could enhance the epithelial-mesenchymal transition (EMT) in cancer cells. Moreover, CTBP1 silencing reversed the effect of BTR on EMT progression in endometrial carcinoma cells. Conclusion: This study indicates that BTR could act as a carcinogen to promote the development of endometrial carcinoma mainly through CTBP1-mediated EMT, which deserves more attention.

scholarly journals MicroRNA-330-3p promotes brain metastasis and epithelial-mesenchymal transition via GRIA3 in non-small cell lung cancer

Aging ◽  
2019 ◽  
Vol 11 (17) ◽  
pp. 6734-6761 ◽  
Author(s):  
Chunhua Wei ◽  
Ruiguang Zhang ◽  
Qian Cai ◽  
Xican Gao ◽  
Fan Tong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition

scholarly journals PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells

2020 ◽  
Vol 295 (40) ◽  
pp. 13798-13811 ◽  
Author(s):  
Yueli Shi ◽  
Xinyu Wang ◽  
Zhiyong Xu ◽  
Ying He ◽  
Chunyi Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Effector Proteins ◽  
Scaffolding Protein ◽  
Migration And Invasion ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Smad3 Protein

Transforming growth factor β (TGFβ) signaling plays an important role in regulating tumor malignancy, including in non–small cell lung cancer (NSCLC). The major biological responses of TGFβ signaling are determined by the effector proteins SMAD2 and SMAD3. However, the regulators of TGFβ–SMAD signaling are not completely revealed yet. Here, we showed that the scaffolding protein PDLIM5 (PDZ and LIM domain protein 5, ENH) critically promotes TGFβ signaling by maintaining SMAD3 stability in NSCLC. First, PDLIM5 was highly expressed in NSCLC compared with that in adjacent normal tissues, and high PDLIM5 expression was associated with poor outcome. Knockdown of PDLIM5 in NSCLC cells decreased migration and invasion in vitro and lung metastasis in vivo. In addition, TGFβ signaling and TGFβ-induced epithelial–mesenchymal transition was repressed by PDLIM5 knockdown. Mechanistically, PDLIM5 knockdown resulted in a reduction of SMAD3 protein levels. Overexpression of SMAD3 reversed the TGFβ-signaling-repressing and anti-migration effects induced by PDLIM5 knockdown. Notably, PDLIM5 interacted with SMAD3 but not SMAD2 and competitively suppressed the interaction between SMAD3 and its E3 ubiquitin ligase STUB1. Therefore, PDLIM5 protected SMAD3 from STUB1-mediated proteasome degradation. STUB1 knockdown restored SMAD3 protein levels, cell migration, and invasion in PDLIM5-knockdown cells. Collectively, our findings indicate that PDLIM5 is a novel regulator of basal SMAD3 stability, with implications for controlling TGFβ signaling and NSCLC progression.

scholarly journals BMI1,ALDH1A1, andCD133Transcripts Connect Epithelial-Mesenchymal Transition to Cancer Stem Cells in Lung Carcinoma

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Ana Koren ◽  
Matija Rijavec ◽  
Izidor Kern ◽  
Eva Sodja ◽  
Peter Korosec ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mrna Expression ◽  
Whole Blood ◽  
Epithelial Mesenchymal Transition ◽  
Immunohistochemical Analysis ◽  
Underlying Mechanism ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Cellular Models ◽  
Nsclc Patients

Epithelial-mesenchymal transition (EMT) is the underlying mechanism of tumor invasion and metastasis. Evidences from lung cancer cellular models show EMT can trigger conversion to a cancer stem cell (CSC) phenotype. In this study, we assessed mRNA expression levels of EMT-inducing transcription factors (BMI1,TWIST1), CSC (CD133,ALDH1A1), and epithelial (EpCAM) markers in primary tumor and whole blood samples obtained from 57 patients with operable non-small-cell lung cancer (NSCLC) as well as in circulating tumor cells (CTCs) of 13 patients with metastatic disease; then possible associations between marker expressions were evaluated. In primary tumors as well as in whole blood, correlations betweenBMI1andALDH1A1and betweenBMI1andCD133mRNA expressions were identified. No correlations betweenTWIST1and CSC markers were observed.BMI1mRNA expression in tumors positively correlated withBMI1mRNA expression in blood. The immunohistochemical analysis confirmed coexpression of BMI1 and CSC markers in tumors. Gene expression profiling in CTCs revealed upregulated expression of EMT/CSC markers in CTCs. Our results suggest CSCs are present in both, tumor tissue and blood of NSCLC patients, whereas Bmi1 may play an important role in initiation and maintenance of CSCs and might be involved in the blood-borne dissemination of NSCLC.

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