Reduced LINC00467 Elevates microRNA-125a-3p to Suppress Cisplatin Resistance in Non-Small Cell Lung Cancer Through Inhibiting Sirtuin 6 and Inactivating the ERK1/2 Signaling Pathway

Background: Cassane-type diterpenoids are widely distributed in the medical plants of genus Caesalpinia. To date, plenty of cassane diterpenoids have been isolated from the genus Caesalpinia, and some of them were documented to exhibit multiple biological activities. However, the effects of these compounds on autophagy have never been reported. Objective: To investigate the effects and mechanisms of the cassane diterpenoids including Phanginin R (PR) on autophagy in Non-Small Cell Lung Cancer (NSCLC) A549 cells. Methods: Western blot analysis and immunofluorescence assay were performed to investigate the effects of the compounds on autophagic flux in A549 cells. The pathway inhibitor and siRNA interference were used to investigate the mechanism of PR. MTT assay was performed to detect cell viability. Results: PR treatment upregulated the expression of phosphatidylethanolamine-modified microtubule-associated protein Light-Chain 3 (LC3-II) in A549 cells. Immunofluorescence assay showed that PR treatment increased the production of red-fluorescent puncta in mRFP-GFP-LC3 plasmid-transfected cells, indicating PR promoted autophagic flux in A549 cells. PR treatment activated the c-Jun N-terminal Kinase (JNK) signaling pathway while it did not affect the classical Akt/mammalian Target of Rapamycin (mTOR) pathway. Pretreatment with the JNK inhibitor SP600125 or siRNA targeting JNK or c-Jun suppressed PR-induced autophagy. In addition, cotreatment with the autophagy inhibitor Chloroquine (CQ) or inhibition of the JNK/c-Jun signaling pathway increased PR-induced cytotoxicity. Conclusion: PR induced cytoprotective autophagy in NSCLC A549 cells via the JNK/c-Jun signaling pathway, and autophagy inhibition could further improve the anti-cancer potential of PR.

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Midazolam increases cisplatin-sensitivity in non-small cell lung cancer (NSCLC) via the miR-194-5p/HOOK3 axis

Cancer Cell International ◽

10.1186/s12935-021-02104-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Tingting Sun ◽

Jing Chen ◽

Xuechao Sun ◽

Guonian Wang

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cell Apoptosis ◽

Cisplatin Resistance ◽

Small Cell ◽

Luciferase Reporter ◽

Small Cell Lung ◽

Cisplatin Sensitivity

Abstract Backgrounds As previously reported, midazolam anesthesia exerts tumor-suppressing effects in non-small cell lung cancer (NSCLC), but the regulating effects of this drug on cisplatin-resistance in NSCLC have not been studied. Thus, we designed this study to investigate this issue and preliminarily delineate the potential molecular mechanisms. Methods We performed MTT assay and trypan blue staining assay to measure cell proliferation and viability. Cell apoptosis was examined by FCM. qRT-PCR and immunoblotting were performed to determine the expression levels of genes. The targeting sites between genes were predicted by bioinformatics analysis and were validated by dual-luciferase reporter gene system assay. Mice tumor-bearing models were established and the tumorigenesis was evaluated by measuring tumor weight and volume. Immunohistochemistry (IHC) was used to examine the pro-proliferative Ki67 protein expressions in mice tumor tissues. Results The cisplatin-resistant NSCLC (CR-NSCLC) cells were treated with high-dose cisplatin (50 μg/ml) and low-dose midazolam (10 μg/ml), and the results showed that midazolam suppressed cell proliferation and viability, and promoted cell apoptosis in cisplatin-treated CR-NSCLC cells. In addition, midazolam enhanced cisplatin-sensitivity in CR-NSCLC cell via modulating the miR-194-5p/hook microtubule-tethering protein 3 (HOOK3) axis. Specifically, midazolam upregulated miR-194-5p, but downregulated HOOK3 in the CR-NSCLC cells, and further results validated that miR-194-5p bound to the 3’ untranslated region (3’UTR) of HOOK3 mRNA for its inhibition. Also, midazolam downregulated HOOK3 in CR-NSCLC cells by upregulating miR-194-5p. Functional experiments validated that both miR-194-5p downregulation and HOOK3 upregulation abrogated the promoting effects of midazolam on cisplatin-sensitivity in CR-NSCLC cells. Conclusions Taken together, this study found that midazolam anesthesia reduced cisplatin-resistance in CR-NSCLC cells by regulating the miR-194-5p/HOOK3 axis, implying that midazolam could be used as adjuvant drug for NSCLC treatment in clinical practices.

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Exploration in the mechanism of fucosterol for the treatment of non-small cell lung cancer based on network pharmacology and molecular docking

Scientific Reports ◽

10.1038/s41598-021-84380-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaoling Li ◽

Baixin Lin ◽

Zhiping Lin ◽

Yucui Ma ◽

Qu Wang ◽

...

Keyword(s):

Lung Cancer ◽

Molecular Docking ◽

Small Cell Lung Cancer ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Small Cell ◽

Erk Signaling ◽

Network Pharmacology ◽

Protein Interaction Data ◽

Small Cell Lung

AbstractFucosterol, a sterol isolated from brown algae, has been demonstrated to have anti-cancer properties. However, the effects and underlying molecular mechanism of fucosterol on non-small cell lung cancer remain to be elucidated. In this study, the corresponding targets of fucosterol were obtained from PharmMapper, and NSCLC related targets were gathered from the GeneCards database, and the candidate targets of fucosterol-treated NSCLC were predicted. The mechanism of fucosterol against NSCLC was identified in DAVID6.8 by enrichment analysis of GO and KEGG, and protein–protein interaction data were collected from STRING database. The hub gene GRB2 was further screened out and verified by molecular docking. Moreover, the relationship of GRB2 expression and immune infiltrates were analyzed by the TIMER database. The results of network pharmacology suggest that fucosterol acts against candidate targets, such as MAPK1, EGFR, GRB2, IGF2, MAPK8, and SRC, which regulate biological processes including negative regulation of the apoptotic process, peptidyl-tyrosine phosphorylation, positive regulation of cell proliferation. The Raf/MEK/ERK signaling pathway initiated by GRB2 showed to be significant in treating NSCLC. In conclusion, our study indicates that fucosterol may suppress NSCLC progression by targeting GRB2 activated the Raf/MEK/ERK signaling pathway, which laying a theoretical foundation for further research and providing scientific support for the development of new drugs.

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SIRT6 through PI3K /Akt/ mTOR Signaling Pathway to Enhance Radiosensitivity of Non‐Small Cell Lung Cancer and Inhibit Tumor Progression

IUBMB Life ◽

10.1002/iub.2511 ◽

2021 ◽

Author(s):

Lianggeng Xiong ◽

Binxin Tan ◽

Xiubing Lei ◽

Biao Zhang ◽

Wenting Li ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Tumor Progression ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Small Cell ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Small Cell Lung

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ARHGAP10 inhibits the epithelial–mesenchymal transition of non-small cell lung cancer by inactivating PI3K/Akt/GSK3β signaling pathway

Cancer Cell International ◽

10.1186/s12935-021-02022-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lan-Lan Lin ◽

Fan Yang ◽

Dong-Huan Zhang ◽

Cong Hu ◽

Sheng Yang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Rho Gtpase ◽

Epithelial Mesenchymal Transition ◽

Essential Element ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition

Abstract Background Rho GTPase activating protein 10 (ARHGAP10) has been implicated as an essential element in multiple cellular process, including cell migration, adhesion and actin cytoskeleton dynamic reorganization. However, the correlation of ARHGAP10 expression with epithelial–mesenchymal transition (EMT) in lung cancer cells is unclear and remains to be elucidated. Herein, we investigated the relationship between the trait of ARHGAP10 and non-small cell lung cancer (NSCLC) pathological process. Methods Immunohistochemistry was conducted to evaluate the expression of ARHGAP10 in NSCLC tissues. CCK-8 assays, Transwell assays, scratch assays were applied to assess cell proliferation, invasion and migration. The expression levels of EMT biomarkers and active molecules involved in PI3K/Akt/GSK3β signaling pathway were examined through immunofluorescence and Western blot. Results ARHGAP10 was detected to be lower expression in NSCLC tissues compared with normal tissues from individuals. Moreover, overexpression of ARHGAP10 inhibited migratory and invasive potentials of A549 and NCI-H1299 cells. In addition, ARHGAP10 directly mediated the process of EMT via PI3K/Akt/GSK3β pathway. Meanwhile, activation of the signaling pathway of insulin-like growth factors-1 (IGF-1) reversed ARHGAP10 overexpression regulated EMT in NSCLC cells. Conclusion ARHGAP10 inhibits the epithelial–mesenchymal transition in NSCLC via PI3K/Akt/GSK3β signaling pathway, suggesting agonist of ARHGAP10 may be an optional remedy for NSCLC patients than traditional opioids.

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