Metformin blocks migration and invasion of tumour cells by inhibition of matrix metalloproteinase‐9 activation through a calcium and protein kinase Cα‐dependent pathway: phorbol‐12‐myristate‐13‐acetate‐induced/extracellular signal‐regulated kinase/activator protein‐1

摘要: Background and purpose Population studies have revealed that treatment with the anti-diabetic drug metformin is significantly associated reduced cancer risk, but underlying mode of action has not been elucidated. The aim our study was to determine effect on tumour invasion migration, possible mechanisms, using human fibrosarcoma HT-1080 cells. Experimental approach We employed invasion, migration gelatin zymography assays characterize Transient transfection were performed gene promoter activities, immunoblot analysis its molecular mechanisms action. Key results Metformin inhibited by cells at sub-toxic concentrations. In these cells, also suppressed phorbol-12-myristate-13-acetate (PMA)-enhanced levels matrix metalloproteinases-9 (MMP-9) protein, mRNA transcription activity through suppression activator protein-1 (AP-1) activation. addition, strongly repressed PMA-induced phosphorylation extracellular signal-regulated kinase (ERK), c-Jun N-terminal (JNK) protein C(PKC)alpha, whereas p38 mitogen-activated affected metformin. decreased Ca(2+) influx. Furthermore, an intracellular chelator (BAPTA-AM) or a selective calmodulin antagonist (W7) markedly MMP-9 secretion cell as well activation ERK JNK/AP-1. Conclusions implications via Ca(2+)-dependent PKCalpha/ERK JNK/AP-1-signalling pathways. therefore potential be potent anti-cancer in therapeutic strategies for metastasis.