scholarly journals Halofuginone Sensitizes Lung Cancer Organoids to Cisplatin via Suppressing PI3K/AKT and MAPK Signaling Pathways

2021 ◽  
Vol 9 ◽  
Author(s):  
Hefei Li ◽  
Yushan Zhang ◽  
Xiaomei Lan ◽  
Jianhua Yu ◽  
Changshuang Yang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Lung Cancer Cells ◽  
Dependent Manner ◽  
New Strategy ◽  
Resistant Patient ◽  
Mapk Signaling Pathways

Lung cancer is the leading cause of cancer death worldwide. Cisplatin is the major DNA-damaging anticancer drug that cross-links the DNA in cancer cells, but many patients inevitably develop resistance with treatment. Identification of a cisplatin sensitizer might postpone or even reverse the development of cisplatin resistance. Halofuginone (HF), a natural small molecule isolated from Dichroa febrifuga, has been found to play an antitumor role. In this study, we found that HF inhibited the proliferation, induced G0/G1 phase arrest, and promoted apoptosis in lung cancer cells in a dose-dependent manner. To explore the underlying mechanism of this antitumor effect of halofuginone, we performed RNA sequencing to profile transcriptomes of NSCLC cells treated with or without halofuginone. Gene expression profiling and KEGG analysis indicated that PI3K/AKT and MAPK signaling pathways were top-ranked pathways affected by halofuginone. Moreover, combination of cisplatin and HF revealed that HF could sensitize the cisplatin-resistant patient-derived lung cancer organoids and lung cancer cells to cisplatin treatment. Taken together, this study identified HF as a cisplatin sensitizer and a dual pathway inhibitor, which might provide a new strategy to improve prognosis of patients with cisplatin-resistant lung cancer.

scholarly journals Dictamnine, a Novel c-Met Inhibitor, Suppresses the Proliferation of Lung Cancer Cells by Downregulating the PI3K/Ak/mTOR and MAPK Signaling Pathways

2020 ◽  
Author(s):  
Jiaojiao Yu ◽  
Lijing Zhang ◽  
Jun Peng ◽  
Richard Ward ◽  
Peiqi Hao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Colony Formation ◽  
Mapk Signaling ◽  
Lung Cancer Cells ◽  
Root Bark ◽  
Met Inhibitor ◽  
Mapk Signaling Pathways

Abstract Background: Dictamnine (Dic), a naturally occurring furoquinoline alkaloid isolated from the root bark of Dictamnus dasycarpus Turcz., is reported to display a wide range of potential pharmacological properties including anticancer activity against multiple cancer types. However, little is known about the direct target proteins and anticancer mechanisms of Dic.Methods: Anticancer effects of Dic and chemotherapy resistance of lung cancer were determined by CCK8, EdU and apoptosis assay. Boyden chamber migration and invasion, wound healing assay, plate colony formation and sphere formation assay were performed to explore the effects of Dic on metastasis and stemness of lung cancer cells. Protein docking analysis, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used for prediction and confirmation of the interaction between Dic and c-Met. qRT-PCR, Western blotting and immunohistochemistry (IHC) were used in mechanism investigation. Tumor xenograft model was used to evaluate the anti-tumor effects of Dic in vivo.Results: Dic was found to suppress the proliferation of lung cancer cells and attenuate the activation of the PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) signaling pathways by directly inhibiting the phosphorylation and activation of the receptor tyrosine kinase c-Met. Moreover, Dic treatment significantly inhibited the colony formation, migration, invasion, stemness, adhesive ability, epithelial-mesenchymal transition and in vivo xenograft tumor growth of A549 lung cancer cells. Notably, the combination of Dic and gefitinib synergistically inhibited the cell proliferation, induced apoptosis, and suppressed the PI3K/Akt/mTOR and MAPK signaling pathways in PC9 gefitinib resistant cells.Conclusions: In conclusion, Dic was identified as a novel c-Met inhibitor and our results suggest the potential use of Dic as a new therapeutic agent in the treatment of lung cancer or other cancers with overactive c-Met pathway.

scholarly journals An Inhibitory Role of Osthole in Rat MSCs Osteogenic Differentiation and Proliferation via Wnt/β-Catenin and Erk1/2-MAPK Pathways

2016 ◽  
Vol 38 (6) ◽  
pp. 2375-2388 ◽  
Author(s):  
Hongyang Hu ◽  
Min Chen ◽  
Guangzu Dai ◽  
Guoqing Du ◽  
Xuezong Wang ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Signaling Pathways ◽  
Western Blotting ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Cell Counting ◽  
Nuclear Antigen ◽  
Dependent Manner ◽  
Alizarin Red ◽  
Mapk Signaling Pathways

Background/Aims: Bone marrow-derived mesenchymal stem cells (MSCs) are responsible for new bone formation during adulthood. Accumulating evidences showed that Osthole promotes the osteogenic differentiation in primary osteoblasts. The aim of this study was to investigate whether Osthole exhibits a potential to stimulate the osteogenic differentiation of MSCs and the underlying mechanism. Methods: MSCs were treated with a gradient concentration of Osthole (6.25 µM, 12.5 µM, and 25 µM). Cell proliferation was assessed by western blotting with the proliferating cell nuclear antigen (PCNA) and Cyclin D1 antibodies, fluorescence activated cell sorting (FACS), and cell counting kit 8 (CCK8). MSCs were cultured in osteogenesis-induced medium for one or two weeks. The osteogenic differentiation of MSCs was estimated by Alkaline Phosphatase (ALP) staining, Alizarin red staining, Calcium influx, and quantitative PCR (qPCR). The underlying mechanism of Osthole-induced osteogenesis was further evaluated by western blotting with antibodies in Wnt/β-catenin, PI3K/Akt, BMPs/smad1/5/8, and MAPK signaling pathways. Results: Osthole inhibited proliferation of rat MSCs in a dose-dependent manner. Osthole suppressed osteogenic differentiation of rat MSCs by down-regulating the activities of Wnt/β-catenin and Erk1/2-MAPK signaling. Conclusions: Osthole inhibits the proliferation and osteogenic differentiation of rat MSCs, which might be mediated through blocking the Wnt/β-catenin and Erk1/2-MAPK signaling pathways.

scholarly journals Wharton Jelly Stem Cells inhibits AGS Gastric Cancer Cells through Induction of Apoptosis and Modification of MAPK and NF‑κB Signaling Pathways

2021 ◽  
Author(s):  
Samaneh Abbasi ◽  
Reza Bazyar ◽  
Mohammad Ali Saremi ◽  
Gholamhoseen Alishiri ◽  
Nasrin Seyyedsani ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cell Line ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Induction Of Apoptosis ◽  
Mapk Signaling Pathways

Abstract Background and aim: Gastric cancer) GC) is one of the most common cancer with high mortality worldwide. The human Wharton's jelly stem cells (hWJSCs) can inhibit several cancer cells through several molecular pathways. Therefore, the present study aimed to investigate anticancer effects of hWJSCs conditioned medium (hWJSC-CM) and cell-free lysate (hWJSC-CL) against of GC cell line AGS and underlying signaling pathways. Methods: In this study, we evaluated the effects of hWJSC-CM and hWJSC-CL on viability, proliferation, migration, invasion, apoptosis, and MAPK and NF‑κB signaling pathways in AGS cells. Moreover, mRNA expression of genes involved in apoptosis (BAX, BCL2, SMAC, and SURVIVIN), as well as expression of proteins involved in NF-κB and MAPK signaling pathways were evaluated. Results: The obtained results showed that the hWJSC-CM and hWJSC-CL decreased viability, migration, and invasion of GC cell line AGS in a concentration and time dependent manner. We observed that the hWJSC-CM and hWJSC-CL induced apoptosis pathway through regulation of apoptosis involved genes mRNA expression. In addition, the hWJSC-CM and hWJSC-CL suppressed NF-κB signaling pathways as well as promoted MAPK signaling pathways. Conclusions: In general, our study suggested that the hWJSC-CM and hWJSC-CL inhibits proliferation and viability of GC cell line AGS through induction of apoptosis, as well as modification of NF-κB and MAPK signaling pathways.

scholarly journals Platycodin-D Induced Autophagy in Non-Small Cell Lung Cancer Cells via PI3K/Akt/mTOR and MAPK Signaling Pathways

2015 ◽  
Vol 6 (7) ◽  
pp. 623-631 ◽  
Author(s):  
Ruolin Zhao ◽  
Meijuan Chen ◽  
Zequn Jiang ◽  
Fengming Zhao ◽  
Beili Xi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cell Lung Cancer ◽  
Mapk Signaling ◽  
Small Cell ◽  
Small Cell Lung ◽  
Platycodin D ◽  
Mapk Signaling Pathways

scholarly journals Sevoflurane inhibits proliferation, invasion, but enhances apoptosis of lung cancer cells by Wnt/β-catenin signaling via regulating lncRNA PCAT6/ miR-326 axis

2020 ◽  
Vol 15 (1) ◽  
pp. 159-172
Author(s):  
Guoning Su ◽  
Zhibing Yan ◽  
Min Deng
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Volatile Anesthetic ◽  
Lung Cancer Cells ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Luciferase Reporter Gene ◽  
Western Blot Assay ◽  
Gene Assay ◽  
Cancer Tissues

AbstractSevoflurane was frequently used as a volatile anesthetic in cancer surgery. However, the potential mechanism of sevoflurane on lung cancer remains largely unclear. In this study, lung cancer cell lines (H446 and H1975) were treated by various concentrations of sevoflurane. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assessment and colony formation assay were performed to detect the cell viability and proliferation, separately. Also, transwell assay or flow cytometry assay was applied as well to evaluate the invasive ability or apoptosis in lung cancer cells, respectively. Western blot assay was employed to detect the protein levels of β-catenin and Wnt5a. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the expression level of prostate cancer-associated transcript 6 (PCAT6) and miR-326 in lung cancer tissues and cells. The target interaction between miR-326 and PCAT6 or Wnt5a was predicted by bioinformatics analysis and verified by the dual-luciferase reporter gene assay. Sevoflurane inhibited the abilities on viability, proliferation, invasion, and activation of Wnt/β-catenin signaling, but promoted apoptosis of H446 and H1975 cells in a dose-dependent manner. The expression of PCAT6 was increased in lung cancer tissues and cells, except for that of miR-326. Besides, sevoflurane could lead to expressed limitation of PCAT6 or improvement of miR-326. This process presented a stepwise manner. Up-regulation of PCAT6 restored the suppression of sevoflurane on abilities of proliferation, invasion, rather than apoptosis, and re-activated the Wnt5a/β-catenin signaling in cells. Moreover, the putative binding sites between miR-326 and PCTA6 or Wnt5a were predicted by starBase v2.0 software online. PCAT6 suppressing effects on cells could be reversed by pre-treatment with miR-326 vector. The promotion of Wnt5a inverted effects led from miR-326 or sevoflurane. Our study indicated that sevoflurane inhibited the proliferation, and invasion, but enhanced the apoptosis in lung cancer cells by regulating the lncRNA PCAT6/miR-326/Wnt5a/β-catenin axis.

scholarly journals Targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy

Biology Open ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. bio053298
Author(s):  
Jingjing Wu ◽  
Youqile Wu ◽  
Xuemei Lian
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Cell Viability ◽  
Er Stress ◽  
Cancer Cells ◽  
Lung Tumor ◽  
Lung Cancer Cells ◽  
Dependent Manner ◽  
Mice Model ◽  
Targeted Inhibition

ABSTRACTThis study investigated the pathophysiological role of GRP78 in the survival of lung cancer cells. Lung cancer patient data from public databases were used to analyze the expression of GRP78 and its influence on prognoses. In vivo, GRP78 protein expression was analyzed in an established urethane-induced lung tumor mouse model. In vitro, the effects of targeted inhibition of GRP78 by HA15 in lung cancer cells were assessed, with cell viability analyzed using a CCK-8 assay, cell proliferation using an EdU assay, apoptosis and cell cycle using flow cytometry, subcellular structure using electron microscopy, and relative mRNA and protein expression using RT-PCR, western blotting or immunofluorescence assays. The results showed that GRP78 was highly expressed in the lung tissue of lung cancer mice model or patients, and was associated with a poor prognosis. After inhibition of GRP78 in lung cancer cells by HA15, cell viability was decreased in a dose- and time-dependent manner, proliferation was suppressed and apoptosis promoted. Unfolded protein response signaling pathway proteins were activated, and the autophagy-related proteins and mRNAs were upregulated. Therefore, targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy.

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