title: Methotrexate induces apoptosis in nasal polyps via caspase cascades and both mitochondria-mediated and p38 mitogen-activated protein kinases/Jun N-terminal kinase pathways.
abstract: BACKGROUND
  Methotrexate (MTX) is a very effective treatment for chronic inflammatory diseases that induces apoptosis in nasal polyps (NPs). However, the precise apoptotic pathway in NPs remains unclear. The aim of this study was to identify the apoptotic signaling pathways  activated by MTX in NPs.
  
  
  METHODS
  NP tissues were organ cultured using an air-liquid interface method. Cultures were maintained in the presence or absence of MTX (10 or 100 μM) for 24 hours. To investigate apoptotic signaling in NPs, we performed reverse transcription-polymerase  chain reaction and Western blotting.
  
  
  RESULTS
  MTX-treated NPs contained significantly increased amounts of the active forms of caspase 8, caspase 9, and caspase 3 and displayed increased cleavage of poly(ADP-ribose) polymerase. Expression of the proapoptotic molecules Bax  and Bad at the mRNA and protein levels and of the activated molecules p-Bad and tBid was significantly higher in MTX-treated NPs than in nontreated NPs. In contrast, expression of the antiapoptotic molecule Bcl-2 at the mRNA and protein levels was significantly lower in MTX-treated NPs than  in nontreated NPs. Expression of the phosphorylated forms of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) was significantly higher in MTX-treated NPs than in nontreated NPs. In contrast, expression of the phosphorylated form of Akt was significantly lower in  MTX-treated NPs than in nontreated NPs.
  
  
  CONCLUSIONS
  MTX induces apoptosis in NPs via caspase cascades and both mitochondria-mediated and p38 MAPK/JNK pathways. We suggest that MTX can be used to treat NPs.
authors: Departments of Otorhinolaryngology-Head and Neck Surgery, Inje University, College of Medicine, Pusan Paik Hospital, Busan, Korea.
authors: Hong Wook
authors: HW
authors: Cho
authors: Seong Kook
authors: SK
authors: Park
authors: Kyung Wook
authors: KW
authors: Heo
authors: Dae Young
authors: DY
authors: Hur
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008727:Methotrexate / Q000627:therapeutic use*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009298:Nasal Polyps / Q000188:drug therapy* / Q000473:pathology; D009924:Organ Culture Techniques; D010256:Paranasal Sinuses / Q000187:drug effects* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D008727:Methotrexate