title: Antimetastatic potential of cardiotoxin III involves inactivation of PI3K/Akt and p38 MAPK signaling pathways in human breast cancer MDA-MB-231 cells.
abstract: OBJECTIVE
  The aim of this study is to determine whether cardiotoxin III (CTX III) inhibited the metastasis in MDA-MB-231 cells and to further explain its possible mechanisms.
  
  
  METHODS
  The MTT assay, wound healing assay, Boyden chamber invasion assay, zymography analysis, reverse transcriptase polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), inhibitor assay, and Western blot analysis were used to reveal molecular events of CTX III in this study.
  
  
  RESULTS
  During treatment with non-toxic doses of CTX III, not only cell migration and invasion were markedly suppressed but the expression/activity of matrix metalloproteinase-9 (MMP-9) was also significantly and selectively suppressed in a concentration-dependent manner. In addition, CTX III decreased the nuclear protein level of nuclear factor kappa B (NF-κB), and pretreatment with NF-κB inhibitor (PDTC) or IκB protease inhibitor (TPCK) also reduced MMP-9 expression/activity and cell migration. Our biochemical assays indicated that CTX III potently suppressed the phosphorylation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositide-3-kinase (PI3K) and Akt. Additionally, the treatment of inhibitors specific for p38 MAPK (SB203580) or PI3K (wortmannin) to cells could result in a reduced expression of NF-κB and MMP-9 expression, concomitantly with an inhibition on cell metastasis.
  
  
  CONCLUSIONS
  These results demonstrated that CTX III inhibition of MDA-MB-231 cells may occur through inactivation of both PI3K/Akt and p38 MAPK signaling pathways, exerting inhibitory effects on NF-κB transcriptional factor, thereby decreasing the activity of MMP-9 and then posing an anti-metastatic effect in the cells.
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC.
authors.forename: Kuei-Li
authors.initials: KL
authors.lastname: Lin
authors.forename: Ching-Ming
authors.initials: CM
authors.lastname: Chien
authors.forename: Chi-Ying
authors.initials: CY
authors.lastname: Hsieh
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
authors.forename: Shinne-Ren
authors.initials: SR
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004179:Cobra Cardiotoxin Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004179:Cobra Cardiotoxin Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C082202:cardiotoxin III, Naja naja atra