title: Pirfenidone plays a biphasic role in inhibition of epithelial-mesenchymal transition in non-small cell lung cancer.
abstract: Epithelial to mesenchymal transition (EMT) relates to both organ fibrosis and malignant behavior of cancer. Pirfenidone (PFD) is an anti-fibrotic agent for idiopathic pulmonary fibrosis and one of its functions may be to inhibit fibrotic EMT. This study aimed to investigate the possibility that PFD might exert an anti-tumor effect through inhibition of EMT in non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo.
  
  
  
  NSCLC cells (A549, NCI-H358) were used to evaluate PFD effects on TGF-β1 induced phenotypic changes. Possible TGF-β1 signaling pathways modulated by PFD were evaluated. The effects of PFD on EMT induced by an anti-cancer drug was also analyzed. The impact of PFD on tumor growth in nude mice as well as on EMT change in vivo was also determined.
  
  
  
  PFD significantly inhibited TGF-β1-induced EMT. Smad2 phosphorylation and TGF-β1 receptor I expression were also inhibited as was translocation of Smad2 from the cytoplasm into the nucleus. Carboplatin induced elevation of TGF-β1 production from cancer cells together with induction of EMT, which were suppressed by co-treatment with PFD. In in vivo examination, PFD alone did not inhibit tumor progression whereas its combination with carboplatin significantly decreased tumor growth. Immunohistological analysis showed that PFD suppressed EMT change induced by carboplatin.
  
  
  
  PFD could attenuate the EMT process induced not only by exogenous TGF-β1 but also by paracrine TGF-β produced from NSCLC cells. PFD may be a promising new therapeutic agent for the treatment of NSCLC through the regulation of EMT.
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Fujiwara
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: yshintani@thoracic.med.osaka-u.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shintani
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Funaki
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Minami
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Meinoshin
authors.initials: M
authors.lastname: Okumura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D011728:Pyridones; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D016190:Carboplatin; C093844:pirfenidone
keywords: Chemoresistance; Epithelial-mesenchymal transition; Non-small-cell lung cancer; Pirfenidone; TGF-β