Cardiotoxin III Inhibits Hepatocyte Growth Factor-Induced Epithelial-Mesenchymal Transition and Suppresses Invasion of MDA-MB-231 Cells.
The epithelial-mesenchymal transition (EMT) is the first step required for breast cancer to initiate metastasis. In this study, hepatocyte growth factor (HGF) was used as a metastatic inducer of MDA-MB-231 cells. Cardiotoxin III (CTX III) inhibited HGF-induced morphological changes and upregulation of E-cadherin with the concomitant decrease in N-cadherin and Vimentin protein levels, resulting in inhibition of cell migration and invasion. CTX III-induced downregulation of transcription factors, Snail, Twist, and Slug, in MDA-MB-231 cells. CTX III suppressed c-Met phosphorylation and downstream activation of phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2. The c-Met specific inhibitor PHA665752 attenuated ERK1/2 and Akt phosphorylation, cell migration and invasion, as well as the expressional changes of EMT markers induced by HGF. Taken together, our data suggest that CTX III suppresses HGF/c-Met-induced cell migration and invasion by reversing EMT, which involves the inactivation of the HGF/c-Met-mediated ERK1/2 and PI3K/Akt pathways in MDA-MB-231 cells.
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
Pei-Chien
PC
Tsai
Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
Yaw-Syan
YS
Fu
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
Long-Sen
LS
Chang
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. shreli@kmu.edu.tw.
Shinne-Ren
SR
Lin
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004179:Cobra Cardiotoxin Proteins / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors; D006801:Humans; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000187:drug effects; D015398:Signal Transduction
D000970:Antineoplastic Agents; D004179:Cobra Cardiotoxin Proteins; C066855:HGF protein, human; D009363:Neoplasm Proteins; C082202:cardiotoxin III, Naja naja atra; D017228:Hepatocyte Growth Factor
Cardiotoxin III; Epithelial-mesenchymal transition; Hepatocyte growth factor/c-Met; MDA-MB-231 cells