Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells.
Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells.
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Chi-Ying
CY
Hsieh
Pei-Chien
PC
Tsai
Chih-Hua
CH
Tseng
Yeh-Long
YL
Chen
Long-Sen
LS
Chang
Shinne-Ren
SR
Lin
D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000077191:Wortmannin; D014945:Wound Healing
D000730:Androstadienes; D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9; D009285:Naphthoquinones; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018808:Transcription Factor AP-1; D000077191:Wortmannin; C073873:naphtho(1,2-b)furan-4,5-dione; C579270:MMP9 protein, human