title: Activation of neutral-sphingomyelinase, MAPKs, and p75 NTR-mediating caffeic acid phenethyl ester-induced apoptosis in C6 glioma cells.
abstract: BACKGROUND
  Caffeic acid phenethyl ester (CAPE), a component of propolis, is reported to possess anti-inflammatory, anti-bacterial, anti-viral, and anti-tumor activities. Previously, our laboratory demonstrated the in vitro and in vivo bioactivity of CAPE and addressed the role of p53 and the p38 mitogen-activated protein kinase (MAPK) pathway in regulating CAPE-induced apoptosis in C6 glioma cells.
  
  
  RESULTS
  C6 cancer cell lines were exposed to doses of CAPE; DNA fragmentation and MAPKs and NGF/P75NTR levels were then determined. SMase activity and ceramide content measurement as well as western blotting analyses were performed to clarify molecular changes. The present study showed that CAPE activated neutral sphingomyelinase (N-SMase), which led to the ceramide-mediated activation of MAPKs, including extracellular signal-regulated kinase (ERK), Jun N-terminus kinase (JNK), and p38 MAPK. In addition, CAPE increased the expression of nerve growth factor (NGF) and p75 neurotrophin receptor (p75NTR). The addition of an N-SMase inhibitor, GW4869, established that NGF/p75NTR was the downstream target of N-SMase/ceramide. Pretreatment with MAPK inhibitors demonstrated that MEK/ERK and JNK acted upstream and downstream, respectively, of NGF/p75NTR. Additionally, CAPE-induced caspase 3 activation and poly [ADP-ribose] polymerase cleavage were reduced by pretreatment with MAPK inhibitors, a p75NTR peptide antagonist, or GW4869.
  
  
  CONCLUSIONS
  Taken together, N-SMase activation played a pivotal role in CAPE-induced apoptosis by activation of the p38 MAPK pathway and NGF/p75NTR may explain a new role of CAPE induced apoptosis in C6 glioma.
authors.forename: Tsui-Hwa
authors.initials: TH
authors.lastname: Tseng
authors.forename: Chien-Heng
authors.initials: CH
authors.lastname: Shen
authors.forename: Wen-Shih
authors.initials: WS
authors.lastname: Huang
authors.forename: Cheng-Nan
authors.initials: CN
authors.lastname: Chen
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Liang
authors.affiliation: Division of Transfusion Medicine, Department of Pathology and Laboratory Medicine; Division of Hematology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. jth.lin@gmail.com.
authors.forename: Tseng-Hsi
authors.initials: TH
authors.lastname: Lin
authors.forename: Hsing-Chun
authors.initials: HC
authors.lastname: Kuo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002109:Caffeic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D002109:Caffeic Acids; D009363:Neoplasm Proteins; D020800:Receptor, Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D013108:Sphingomyelin Phosphodiesterase; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol