title: Thiazolidinediones inhibit REG Ialpha gene transcription in gastrointestinal cancer cells.
abstract: REG (Regenerating gene) Ialpha protein functions as a growth factor for gastrointestinal cancer cells, and its mRNA expression is strongly associated with a poor prognosis in gastrointestinal cancer patients. We here demonstrated that PPARgamma-agonist thiazolidinediones (TZDs) inhibited cell proliferation and REG Ialpha protein/mRNA expression in gastrointestinal cancer cells. TZDs inhibited the REG Ialpha gene promoter activity, via its cis-acting element which lacked PPAR response element and could not bind to PPARgamma, in PPARgamma-expressing gastrointestinal cancer cells. The inhibition was reversed by co-treatment with a specific PPARgamma-antagonist GW9662. Although TZDs did not inhibit the REG Ialpha gene promoter activity in PPARgamma-non-expressing cells, PPARgamma overexpression in the cells recovered their inhibitory effect. Taken together, TZDs inhibit REG Ialpha gene transcription through a PPARgamma-dependent pathway. The TZD-induced REG Ialpha mRNA reduction was abolished by cycloheximide, indicating the necessity of novel protein(s) synthesis. TZDs may therefore be a candidate for novel anti-cancer drugs for patients with gastrointestinal cancer expressing both REG Ialpha and PPARgamma.
authors.affiliation: Department of Advanced Biological Sciences for Regeneration, Kotobiken Medical Laboratories, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Iwao
authors.initials: I
authors.lastname: Takahashi
authors.forename: Shin
authors.initials: S
authors.lastname: Takasawa
authors.forename: Koji
authors.initials: K
authors.lastname: Nata
authors.forename: Naoya
authors.initials: N
authors.lastname: Noguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Nausheen J
authors.initials: NJ
authors.lastname: Shervani
authors.forename: Iwao
authors.initials: I
authors.lastname: Suzuki
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D006801:Humans; D051847:Lithostathine / Q000037:antagonists & inhibitors* / Q000235:genetics; D047495:PPAR gamma / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D051847:Lithostathine; D047495:PPAR gamma; C497617:REG1A protein, human; D012333:RNA, Messenger; D045162:Thiazolidinediones