title: Suppression of EGF-induced tumor cell migration and matrix metalloproteinase-9 expression by capsaicin via the inhibition of EGFR-mediated FAK/Akt, PKC/Raf/ERK, p38 MAPK, and AP-1 signaling.
abstract: METHODS
  Capsaicin is a cancer-suppressing agent. The aim of our study was to determine the effect of capsaicin on tumor invasion and migration; the possible mechanisms involved in this inhibition were investigated in human fibrosarcoma cells.
  
  
  RESULTS
  We employed invasion, migration and gelatin zymography assays to characterize the effect of capsaicin on HT-1080 cells. Transient transfection assays and immunoblot analysis were performed to study its molecular mechanisms of action. Capsaicin inhibited the epidermal growth factor (EGF)-induced activation of matrix metalloproteinase (MMP)-9 and MMP-2, and further inhibited cell invasion and migration. Capsaicin decreased the EGF-induced expression of MMP-9, MMP-2, and MT1-MMP, but did not alter TIMP-1 and TIMP-2 levels. Capsaicin suppressed EGF-induced c-Jun and c-Fos nuclear translocation, and also abrogated the EGF-induced phosphorylation of EGF receptor (EGFR), focal adhesion kinase (FAK), protein kinase C (PKC), phosphatidylinositol 3-Kinase (PI3K)/Akt, extracellular regulated kinase (ERK)1/2, and JNK1/2, an upstream modulator of AP-1. Furthermore, the EGFR inhibitor inhibited EGF-induced MMP-9 expression, as well as AP-1 activity and cell migration.
  
  
  CONCLUSIONS
  Capsaicin inhibited the EGF-induced invasion and migration of human fibrosarcoma cells via EGFR-dependent FAK/Akt, PKC/Raf/ERK, p38 mitogen-activated protein kinase (MAPK), and AP-1 signaling, leading to the down-regulation of MMP-9 expression. These results indicate the role of capsaicin as a potent anti-metastatic agent, which can markedly inhibit the metastatic and invasive capacity of fibrosarcoma cells.
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Yong Pil
authors.initials: YP
authors.lastname: Hwang
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Yun
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Han
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.forename: Gye Yong
authors.initials: GY
authors.lastname: Song
authors.forename: Kwang-Il
authors.initials: KI
authors.lastname: Kwon
authors.forename: Tae Cheon
authors.initials: TC
authors.lastname: Jeong
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D066246:ErbB Receptors / Q000378:metabolism; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006727:Hormone Antagonists; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D002211:Capsaicin