RÉSUMÉ
Drug resistance is one of the leading causes of chemotherapy failure in non-small cell lung cancer (NSCLC) treatment. The purpose of this study was to investigate the role of c-met in human lung cancer cisplatin resistance cell line (A549/DDP) and the reversal mechanism of salvianolic acid A (SAA), a phenolic active compound extracted from Salvia miltiorrhiza. In this study, we found that A549/DDP cells exert up-regulation of c-met by activating the Akt/mTOR signaling pathway. We also show that SAA could increase the chemotherapeutic efficacy of cisplatin, suggesting a synergistic effect of SAA and cisplatin. Moreover, we revealed that SAA enhanced sensitivity to cisplatin in A549/DDP cells mainly through suppression of the c-met/AKT/mTOR signaling pathway. Knockdown of c-met revealed similar effects as that of SAA in A549/DDP cells. In addition, SAA effectively prevented multidrug resistance associated protein1 (MDR1) up-regulation in A549/DDP cells. Taken together, our results indicated that SAA suppressed c-met expression and enhanced the sensitivity of lung adenocarcinoma A549 cells to cisplatin through AKT/mTOR signaling pathway.
Sujet(s)
Adénocarcinome/anatomopathologie , Alcènes/pharmacologie , Antinéoplasiques/pharmacologie , Cisplatine/pharmacologie , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Tumeurs du poumon/anatomopathologie , Polyphénols/pharmacologie , Protéines proto-oncogènes c-met/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Sous-famille B de transporteurs à cassette liant l'ATP/génétique , Sous-famille B de transporteurs à cassette liant l'ATP/métabolisme , Adénocarcinome/traitement médicamenteux , Alcènes/isolement et purification , Lignée cellulaire tumorale , Multirésistance aux médicaments/effets des médicaments et des substances chimiques , Multirésistance aux médicaments/génétique , Synergie des médicaments , Humains , Tumeurs du poumon/traitement médicamenteux , Phytothérapie , Polyphénols/isolement et purification , Protéines proto-oncogènes c-akt/métabolisme , Salvia miltiorrhiza/composition chimique , Sérine-thréonine kinases TOR/métabolisme , Régulation positive/effets des médicaments et des substances chimiques , Régulation positive/génétiqueRÉSUMÉ
The present study was aimed to unravel the inhibitory mechanisms of curcumin for lung cancer metastasis via constructing a miRNA-transcription factor (TF)-target gene network. Differentially expressed miRNAs between human high-metastatic non-small cell lung cancer 95D cells treated with and without curcumin were identified using a TaqMan human miRNA array followed by real-time PCR, out of which, the top 6 miRNAs (miR-302b-3p, miR-335-5p, miR-338-3p, miR-34c-5p, miR-29c-3p and miR-34a-35p) with more verified target genes and TFs than other miRNAs as confirmed by a literature review were selected for further analysis. The miRecords database was utilized to predict the target genes of these 6 miRNAs, TFs of which were identified based on the TRANSFAC database. The findings of the above procedure were used to construct a miRNA-TF-target gene network, among which miR-34a-5p, miR-34c-5p and miR-302b-3p seemed to regulate CCND1, WNT1 and MYC to be involved in Wnt signaling pathway through the LEF1 transcription factor. Therefore, we suggest miR-34a-5p/miR-34c-5p/miR-302b-3p -LEF1-CCND1/WNT1/MYC axis may be a crucial mechanism in inhibition of lung cancer metastasis by curcumin.
Sujet(s)
Antinéoplasiques/pharmacologie , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Curcumine/pharmacologie , Réseaux de régulation génique/effets des médicaments et des substances chimiques , Tumeurs du poumon/traitement médicamenteux , microARN/génétique , Invasion tumorale/prévention et contrôle , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/anatomopathologie , Mouvement cellulaire/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Humains , Poumon/effets des médicaments et des substances chimiques , Poumon/anatomopathologie , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Invasion tumorale/génétique , Invasion tumorale/anatomopathologieRÉSUMÉ
MiR-206 is low expression in lung cancers and associated with cancer metastasis. However, the roles of miR-206 in epithelial-mesenchymal transition (EMT) and angiogenesis in lung cancer remain unknown. In this study, we find that hepatocyte growth factor (HGF) induces EMT, invasion and migration in A549 and 95D lung cancer cells, and these processes could be markedly inhibited by miR-206 overexpression. Moreover, we demonstrate that miR-206 directly targets c-Met and inhibits its downstream PI3k/Akt/mTOR signaling pathway. In contrast, miR-206 inhibitors promote the expression of c-Met and activate the PI3k/Akt/mTOR signaling, and this effect could be attenuated by the PI3K inhibitor. Moreover, c-Met overexpression assay further confirms the significant inhibitory effect of miR-206 on HGF-induced EMT, cell migration and invasion. Notably, we also find that miR-206 effectively inhibits HGF-induced tube formation and migration of human umbilical vein endothelial cells (HUVECs), and the mechanism is also related to inhibition of PI3k/Akt/mTOR signaling. Finally, we reveal the inhibitory effect of miR-206 on EMT and angiogenesis in xenograft tumor mice model. Taken together, miR-206 inhibits HGF-induced EMT and angiogenesis in lung cancer by suppressing c-Met/PI3k/Akt/mTOR signaling. Therefore, miR-206 might be a potential target for the therapeutic strategy against EMT and angiogenesis of lung cancer.