title: Esophageal cancer stem cells are suppressed by tranilast, a TRPV2 channel inhibitor.
abstract: BACKGROUND
  Recent evidence suggests that the targeting of membrane proteins specifically activated in cancer stem cells (CSCs) is an important strategy for cancer therapy. The objectives of the present study were to investigate the expression and activity of ion-transport-related molecules in the CSCs of esophageal squamous cell carcinoma.
  
  
  METHODS
  Cells exhibiting strong aldehyde dehydrogenase 1 family member A1 (ALDH1A1) activity were isolated from TE8 cells by fluorescence-activated cell sorting, and CSCs were then generated with the sphere formation assay. The gene expression profiles of CSCs were examined by microarray analysis.
  
  
  RESULTS
  Among TE8 cells, ALDH1A1 messenger RNA and protein levels were higher in CSCs than in non-CSCs. The CSCs obtained were resistant to cisplatin and had the ability to redifferentiate. The results of the microarray analysis revealed that the expression of 50 genes encoding plasma membrane proteins was altered in CSCs, whereas that of several genes related to ion channels, including transient receptor potential vanilloid 2 (TRPV2), was upregulated. The TRPV2 inhibitor tranilast was more cytotoxic at a lower concentration in CSCs than in non-CSCs, and effectively decreased the number of tumorspheres. Furthermore, tranilast significantly decreased the cell population that strongly expressed ALDH1A1 among TE8 cells.
  
  
  CONCLUSIONS
  The results of the present study suggest that TRPV2 is involved in the maintenance of CSCs, and that its specific inhibitor, tranilast, has potential as a targeted therapeutic agent against esophageal squamous cell carcinoma.
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan. shiozaki@koto.kpu-m.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiozaki
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kudou
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ichikawa
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Arita
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kosuga
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Konishi
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Komatsu
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.|Japan Institute for Food Education and Health, St. Agnes' University, Kyoto, 602-8013, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Marunaka
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Eigo
authors.initials: E
authors.lastname: Otsuji
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics; D050697:Retinal Dehydrogenase; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D050916:TRPV Cation Channels; C400769:TRPV2 protein, human; D062367:ortho-Aminobenzoates; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; C012293:tranilast
keywords: Cancer stem cell; Esophageal squamous cell carcinoma; TRPV2; Tranilast