scholarly journals Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1683 ◽  
Author(s):  
Frank Aboubakar Nana ◽  
Marie Vanderputten ◽  
Sebahat Ocak
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cell Lung Cancer ◽  
Therapeutic Target ◽  
Small Cell ◽  
Small Cell Lung

Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC.

scholarly journals P1.07-028 Dual Role of the Focal Adhesion Kinase in Small-Cell Lung Cancer

2017 ◽  
Vol 12 (1) ◽  
pp. S713
Author(s):  
Frank Aboubakar Nana ◽  
Marylène Lecocq ◽  
Maha Ladjemi ◽  
Bruno Detry ◽  
Sebastien Dupasquier ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Dual Role ◽  
Small Cell Lung

scholarly journals Early Candidate Biomarkers of Non–Small Cell Lung Cancer Are Screened and Identified in Premalignant Lung Lesions

2016 ◽  
Vol 16 (1) ◽  
pp. 66-74 ◽  
Author(s):  
Yandong Nan ◽  
Jie Du ◽  
Lijie Ma ◽  
Hua Jiang ◽  
Faguang Jin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cell Lung Cancer ◽  
Src Kinase ◽  
Small Cell ◽  
Normal Lung ◽  
Biological Processes ◽  
Small Cell Lung

A specific protein profile that accompanies neoplastic transformation in the premalignant airway epithelium could provide an opportunity for early diagnosis of lung cancer. The aim of this study was to screen and identify early candidate biomarkers of non–small cell lung cancer. Thirteen non–small cell lung cancer samples were obtained within 30 minutes after a surgical resection. Laser capture microdissection was performed to enrich the normal lung cell and squamous metaplasia or atypical adenomatous hyperplasia cell populations. The resulting tandem mass spectrum was automatically searched for proteins against International Protein Index (IPI) human protein database using the TurboSEQUEST searching engine. The molecular function and biological processes of identified proteins were determined based on universal bioinformatics tools. The 2 proteins of interest, focal adhesion kinase and C-terminal Src kinase, were validated using Western blot method. A total of 863 proteins were identified by automatically searching the tandem mass spectrum, among which 427 were dysregulated expression in premalignant airway epithelium compared with those of normal lung cells. The 427 proteins were mainly distributed in 24 sorts of cellular components, 22 molecular function, 15 biological processes, and 10 significant perturbations of pathways. The most significant network included 48 genes and was related to energy production, cell cytoskeleton, cell adhesion, metabolism, oxidative stress, and small molecule biochemistry. Focal adhesion kinase and C-terminal Src kinase were significantly overexpressed in premalignant lung lesion cells compared with the normal lung cells in 13 cases. We identified that there were 427 proteins involved in non–small cell lung cancer carcinogenic process and confirmed the key biological pathways in premalignant lung tissue. The significantly upregulated focal adhesion kinase and C-terminal Src kinase could be considered as molecular biomarkers for early diagnosis and prognosis of non–small cell lung cancer.

scholarly journals Circ_0005962 functions as an oncogene to aggravate non-small cell lung cancer progression via circ_0005962/miR-382-5p/PDK4 regulatory network

2020 ◽  
Author(s):  
Zhihong Zhang ◽  
Zhenxiu Shan ◽  
Rubin Chen ◽  
Xiaorong Peng ◽  
Bin Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Caspase 3 ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung

AbstractNon-small cell lung cancer (NSCLC) is a leading threat to human lives with high incidence and mortality. Circular RNAs (circRNAs) were reported to play important roles in human cancers. The purpose of this study was to investigate the role of circ_0005962 and explore the underlying functional mechanisms. The expression of circ_0005962, miR-382-5p and pyruvate dehydrogenase kinase 4 (PDK4) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation and cell apoptosis were assessed by cell counting kit-8 (CCK-8) assay and flow cytometry assay, respectively. The protein levels of Beclin 1, light chain3 (LC3-II/LC3-I), PDK4, Cleaved Caspase 3 (C-caspase 3) and proliferating cell nuclear antigen (PCNA) were examined using western blot analysis. Glycolysis was determined according to the levels of glucose consumption and lactate production. The interaction between miR-382-5p and circ_0005962 or PDK4 was predicted by the online tool CircInteractome or starbase and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Xenograft model was constructed to investigate the role of circ_0005962 in vivo. circ_0005962 expressed with a high level in NSCLC tissues and cells. Circ_0005962 knockdown inhibited proliferation, autophagy, and glycolysis but promoted apoptosis in NSCLC cells. MiR-382-5p was targeted by circ_0005962, and its inhibition reversed the role of circ_0005962 knockdown. Besides, PDK4, a target of miR-382-5p, was regulated by circ_0005962 through miR-382-5p, and its overexpression abolished the effects of miR-382-5p reintroduction. Circ_0005962 knockdown suppressed tumor growth in vivo. Circ_0005962 knockdown restrained cell proliferation, autophagy, and glycolysis but stimulated apoptosis through modulating the circ_0005962/miR-382-5p/PDK4 axis. Our study broadened the insights into understanding the mechanism of NSCLC progression.

scholarly journals Molecular Dynamics of A Biglycan-Rosmarinic Acid Complex with Focal Adhesion Kinase for Possible Arrest of Metastasis in Non-Small Cell Lung Cancer (NSCLC): An In- Silico Study

2019 ◽  
Vol 9 (4-A) ◽  
pp. 159-166
Author(s):  
Hyacinth Highland ◽  
Monica Thakur ◽  
Pujan Pandya ◽  
Archana Mankad ◽  
Linz-Buoy George
Keyword(s):  
Lung Cancer ◽  
Molecular Dynamics ◽  
Molecular Docking ◽  
Small Cell Lung Cancer ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cell Lung Cancer ◽  
Rosmarinic Acid ◽  
Small Cell ◽  
Small Cell Lung

Background: Non-small cell lung cancer (NSCLC) is the major cause of mortality all over the world. Significant increase of biglycan is seen in the lung cancer cells when compared with the normal cells. It promotes tumor invasion and metastasis by activating Focal Adhesion Kinase (FAK) signaling pathway. The increased FAK activity may contribute to the metastatic potential of malignant tumors. This study was carried out to establish binding interactions of some selected phytocomponents against biglycan for the possible arrest of metastasis. Methods: Protein-ligand interaction studies were performed using 30 natural compounds from different culinary herbs having potential therapeutic role against the target protein biglycan (BGN). Molegro Virtual Docker (v 5.0) was used as docking tool to evaluate the effectiveness of selected phytocomponents based upon the interaction with the protein’s active site residues with minimal binding energy. Protein-protein docking was performed to observe the interaction of BGN and FAK using Hex (v 8.0.0). Molecular dynamics (10 ns) of BGN-RA-FAK and FAK-RA-BGN was performed in Yasara structure (v 17.8.15) which showed stability of the structure in terms of RMSD values. Results: Molecular docking analysis revealed the selectivity of Rosmarinic acid (RA) towards BGN and FAK. Molecular dynamics trajectory of BGN-RA-FAK and FAK-RA-BGN complexes showed the stability of structure in terms of Time vs Energy and Time vs RMSD values and revealed that binding of RA to BGN will block the interaction of FAK. Conclusions: Hence, investigating the binding interactions of BGN-RA-FAK complex may turn out to be helpful in arresting metastasis in NSCLC. Keywords: Non-small cell lung cancer, Biglycan, Focal adhesion kinase, Phytocomponents, Molecular Docking, Molecular Dynamics

scholarly journals KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway

2020 ◽  
Author(s):  
Wenwen Du ◽  
Jianjie Zhu ◽  
Yuanyuan Zeng ◽  
Ting Liu ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Signaling Pathway ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Small Cell Lung

Abstract In addition to the role of programmed cell death ligand 1 (PD-L1) in facilitating tumour cells escape from immune surveillance, it is considered as a crucial effector in transducing intrinsic signals to promote tumour development. Our previous study has pointed out that PD-L1 promotes non-small cell lung cancer (NSCLC) cell proliferation, but the mechanism remains elusive. Here we first demonstrated that PD-L1 expression levels were positively correlated with p-MerTK levels in patient samples and NSCLC cell lines. In addition, PD-L1 knockdown led to the reduced phosphorylation level of MerTK in vitro. We next showed that PD-L1 regulated NSCLC cell proliferation via Gas6/MerTK signaling pathway in vitro and in vivo. To investigate the underlying mechanism, we unexpectedly found that PD-L1 translocated into the nucleus of cancer cells which was facilitated through the binding of Karyopherin β1 (KPNB1). Nuclear PD-L1 (nPD-L1), coupled with transcription factor Sp1, regulated the synthesis of Gas6 mRNA and promoted Gas6 secretion to activate MerTK signaling pathway. Taken together, our results shed light on the novel role of nPD-L1 in NSCLC cell proliferation and reveal a new molecular mechanism underlying nPD-L1-mediated Gas6/MerTK signaling activation. All above findings provide the possible combinational implications for PD-L1 targeted immunotherapy in the clinic.

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