The impact of metformin and salinomycin on transforming growth factor β-induced epithelial-to-mesenchymal transition in non-small cell lung cancer cell lines

Koeck, Stefan; Amann, Arno; Huber, Julia; Gamerith, Gabriele; Hilbe, Wolfgang; Zwierzina, Heinz

doi:10.3892/ol.2016.4323

Cited by 25 publications

(17 citation statements)

References 27 publications

(24 reference statements)

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“…The cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) with low glucose (GE Healthcare Life Sciences, vienna, Austria), supplemented with 10% fetal calf serum (FCS; Sigma-Aldrich, Munich, Germany) and 100 U/ml penicillin, 100 µg/ml streptomycin and 2 mM Lglutamine (PAA Laboratories; GE Healthcare Life Sciences). The cells were cultivated in cell culture flasks (Falcon ® ; Becton-Dickinson Austria GmbH, Schwechat, Austria) at 37˚C in an atmosphere of 5% CO 2 until the desired cell confluence for further experiments was reached (15).…”

Section: Sample Preparationmentioning

confidence: 99%

miR-768-3p is involved in the proliferation, invasion and migration of non-small cell lung carcinomas

Xie

Chen

et al. 2017

International Journal of Oncology

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Altered microRNA expression has been found to be a common feature of several cancers, including lung carcinomas. However, the possible roles of miR-768-3p in the pathological changes of lung carcinomas are still unknown. The aim of the present study was to investigate the expression and possible effects of miR-768-3p in human non-small cell lung carcinomas (NSCLC). Eighty-three NSCLC patients attending the clinic of Kunming Hospital were invited to participate in the study. Their tumor samples were obtained for qRT-PCR analysis. Human NSCLC cell lines, A549 and HCC4006, were employed and transfected with either miR-768-3p mimics or miR-768-3p antagomir. Following transfection, the in vitro and in vivo proliferation, apoptosis fractions, migration and invasion of NSCLC cells were evaluated. The data revealed that: i) upregulated miR-768-3p in tumors were associated with the clinicopathological features of NSCLC patients; ii) inhibiting miR-768-3p function by miR-768-3p antagomir induced distinctly apoptosis and Fas/FasL expressional alteration of NSCLC cells; iii) miR-768-3p antagomir transduction also decreased the viability, migration and invasion, as well as MMP-2 and MMP-9 activities in A549 and HCC4006 cells; and iv) miR-768-3p antagomir transfection also inhibited the growth and proliferation of NSCLC xenografts in nude mice. The present results suggested that abnormal elevated miR-768-3p in NSCLC tumors and cell lines played important roles in NSCLC carcinogenic progression, and the targeting of miR-768-3p might be a potential therapeutic strategy for the treatment of NSCLC.

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Section: Sample Preparationmentioning

confidence: 99%

miR-768-3p is involved in the proliferation, invasion and migration of non-small cell lung carcinomas

Xie

Chen

et al. 2017

International Journal of Oncology

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“…It blocks different types of tumor cell in the G0/G1 phase or inhibits the G1/S-phase transition in the cell cycle by regulating the expression of cell cycle proteins and their associated factors (25)(26)(27). Metformin also exerts a dose-dependent inhibitory effect on the proliferation of lung cancer cells of various pathological types (28,29). The mechanism may include the activation of the adenosine 5'monophosphate-activated protein kinase (AMPK) pathway (30,31), which reduces the proliferation of tumor cells by inhibiting epidermal growth factor receptor and insulin-like growth factor 1 receptor pathways (26,32,33).…”

Section: Introductionmentioning

confidence: 99%

Metformin reverses the resistance mechanism of lung adenocarcinoma cells that knocks down the Nrf2 gene

et al. 2018

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The nuclear factor, er ythroid 2 like 2 (Nrf2)/antioxidant response element (ARE) pathway has an important role in the drug resistance of adenocarcinoma, and may act via different mechanisms, including the mitogen-activated protein kinase (MAPK) pathway. However, it has remained elusive whether metformin affects Nrf2 and regulates Nrf2/ARE in adenocarcinoma. In the present study, reverse-transcription quantitative polymerase chain reaction, cell transfection, western blot analysis, a Cell Counting kit-8 assay and apoptosis detection were used to investigate the above in the A549 cell line and cisplatin-resistant A549 cells (A549/DDP). The results indicated that Nrf2, glutathione S-transferase α 1 (GSTA1) and ATP-binding cassette subfamily C member 1 (ABCC1) were dose-dependently reduced by metformin, and that the effect in A549 cells was greater than that in A549/DDP cells. Treatment with metformin decreased the proliferation and increased the apoptosis of A549 cells to a greater extent than that of A549/DDP cells, and the effect was dose-dependent. After transfection of A549/DDP cells with Nrf2 short hairpin RNA (shRNA), GSTA1 and ABCC1 were markedly decreased, compared with the shRNA-control group of A549/DDP, and low dose-metformin reduced the proliferation and increased apoptosis of A549/DDP cells. Metformin inhibited the Akt and extracellular signal-regulated kinase (ERK)1/2 pathways in A549 cells and activated the p38 MAPK and c-Jun N-terminal kinase (JNK) pathways. Furthermore, in the presence of metformin, inhibitors of the p38 MAPK and JNK signaling pathway at different concentrations did not affect the levels of Nrf2, but inhibitors of the Akt and ERK1/2 pathway at different doses reduced the expression of Nrf2. In addition, inhibitors of p38 MAPK and JNK did not affect the effect of metformin on Nrf2, while inhibitors of Akt and ERK1/2 dose-dependently enhanced the inhibitory effects of metformin in A549 cells. In conclusion, metformin inhibits the phosphoinositide-3 kinase/Akt and ERK1/2 signaling pathways in A549 cells to reduce the expression of Nrf2, GSTA1 and ABCC1. Metformin also reverses the resistance of A549/DDP cells to platinum drugs, inhibits the proliferation and promotes apoptosis of drug-resistant cells. These results may provide a theoretical basis and therapeutic targets for the clinical treatment of tumors.

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“…Recently, it has been reported that Met reversed EMT phenotype induced with transforming growth factor beta 1 (TGF-β1) in breast, lung, and cervical cancer cells by targeting the mechanisms regulating the expression of E-cadherin. The exposition of tumor cells to Met resulted in suppression of their metastatic properties [8,38].…”

Section: Metformin Inhibits Epithelial-to-mesenchymal Transition (Emtmentioning

confidence: 99%

Metformin in Cervical Cancer: Metabolic Reprogramming

Tyszka-Czochara¹,

Majka²

2019

Metformin [Working Title]

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The reprogrammed metabolism plays a crucial role in intensively proliferating tumor cells to meet high energetic demands and adapt to metastasis and invasion. Metformin may counteract flexible metabolic phenotype of cervical cancer cells by restraining aerobic glycolysis (Warburg effect) and promoting mitochondrial-based metabolism. Metformin inhibits master oncogene c-Myc as well as hypoxia-inducible factor 1 (HIF-1α) and suppresses its downstream glycolytic regulatory enzymes and glucose transporters. Metformin targets bioenergetics of cervical cancer cells with aggressive phenotype and regulates the expression of enzymes controlling tricarboxylic acid cycle (TCA cycle) supplementation with substrates, glucose, and glutamine. The exposition of cervical tumor cells to Metformin alleviates their migratory capacity, restrains epithelial-to-mesenchymal transition (EMT) program implementation, and elucidates oxidative stress, which results in massive cell death due to apoptosis. The metabolic alterations caused by Metformin are specific to cancer cells. In summary, Metformin exerts antitumor effect in cervical cancer cells by regulating specific molecular targets in reprogrammed metabolism. Metformin selectively modulates metabolic pathways and thus may be potentially used in new precisely targeted therapeutic strategies for cervical cancer.

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The impact of metformin and salinomycin on transforming growth factor β-induced epithelial-to-mesenchymal transition in non-small cell lung cancer cell lines

Cited by 25 publications

References 27 publications

miR-768-3p is involved in the proliferation, invasion and migration of non-small cell lung carcinomas

miR-768-3p is involved in the proliferation, invasion and migration of non-small cell lung carcinomas

Metformin reverses the resistance mechanism of lung adenocarcinoma cells that knocks down the Nrf2 gene

Metformin in Cervical Cancer: Metabolic Reprogramming

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