Cardiotoxin III suppresses MDA-MB-231 cell metastasis through the inhibition of EGF/EGFR-mediated signaling pathway.
Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been shown to exhibit anticancer activity. Epidermal growth factor (EGF) and its receptor, EGFR, play roles in cancer metastasis in various tumors. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CTX III on cell migration. CTX III inhibited the EGF-induced activation of matrix metalloproteinase-9 (MMP-9), and further suppressed cell invasion and migration without obvious cellular cytotoxicity. CTX III suppressed EGF-induced nuclear factor-kappaB (NF-κB) nuclear translocation and also abrogated the EGF-induced phosphorylation of EGFR, phosphatidylinositol 3-kinase (PI3K)/Akt, and extracellular regulated kinase (ERK)1/2. In addition, CTX III similar to wortmannin (a PI3K inhibitor) and U0126 (an up-stream kinase regulating ERK1/2 inhibitor) attenuated cell migration and invasion induced by EGF. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-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 occur downstream of EGFR activation. These findings suggest that CTX III inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt, ERK1/2, and NF-κB signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CTX III as a potent anti-metastatic agent in MDA-MB-231 cells.
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Pei-Chien
PC
Tsai
Chi-Ying
CY
Hsieh
Chien-Chih
CC
Chiu
Chih-Kuang
CK
Wang
Long-Sen
LS
Chang
Shinne-Ren
SR
Lin
D000704:Analysis of Variance; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004179:Cobra Cardiotoxin Proteins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010766:Phosphorylation; D011799:Quinazolines; D015398:Signal Transduction / Q000187:drug effects*; D020032:Tyrphostins
D004179:Cobra Cardiotoxin Proteins; D011799:Quinazolines; D020032:Tyrphostins; C082202:cardiotoxin III, Naja naja atra; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9