title: Cardiotoxin III suppresses hepatocyte growth factor-stimulated migration and invasion of MDA-MB-231 cells.
abstract: The hepatocyte growth factor (HGF)/c-Met signalling pathway is deregulated in most cancers and associated with a poor prognosis in breast cancer. Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been shown to exhibit anticancer activity. In this study, we use HGF as an invasive inducer to investigate the effect of CTX III on MDA-MB-231 cells. When cells were treated with non-toxic doses of CTX III, CTX III inhibited the HGF-promoted cell migration and invasion. CTX III significantly suppressed the HGF-induced c-Met phosphorylation and downstream activation of phosphatidylinositol 3-kinase (PI3k)/Akt and extracellular signal-regulated kinase (ERK) 1/2. Additionally, CTX III similar to wortmannin (a PI3K inhibitor) and U0126 (an upstream kinase regulating ERK1/2 inhibitor) attenuated cell migration and invasion induced by HGF. This effect was paralleled by a significant reduction in phosphorylation of IκBα kinase and IκBα and nuclear translocation of nuclear factor κB (NF-κB) as well as a reduction of matrix metalloproteinase-9 (MMP-9) activity. Furthermore, the c-Met inhibitor PHA665752 inhibited HGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of ERK1/2 and PI3K/Akt, suggesting that ERK1/2 and PI3K/Akt activation occurs downstream of c-Met activation. Taken together, these findings suggest that CTX III inhibits the HGF-induced invasion and migration of MDA-MB-231 cells via HGF/c-Met-dependent PI3K/Akt, ERK1/2 and NF-κB signalling pathways, leading to the downregulation of MMP-9 expression.
authors: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Pei-Chien
authors: PC
authors: Tsai
authors: Chiao-Lun
authors: CL
authors: Chu
authors: Chien-Chih
authors: CC
authors: Chiu
authors: Long-Sen
authors: LS
authors: Chang
authors: Shinne-Ren
authors: SR
authors: Lin
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004179:Cobra Cardiotoxin Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D004546:Elapid Venoms / Q000737:chemistry*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D000730:Androstadienes; D002070:Butadienes; D004179:Cobra Cardiotoxin Proteins; D004546:Elapid Venoms; D007211:Indoles; D016328:NF-kappa B; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D013450:Sulfones; C113580:U 0126; C082202:cardiotoxin III, Naja naja atra; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D051058:Oncogene Protein v-akt; D020780:Matrix Metalloproteinase 9; D000077191:Wortmannin
keywords: CTX III; ERK1/2; HGF; MDA-MB-231 cells; PI3K/Akt; c-Met