Thiazolidinediones inhibit REG Ialpha gene transcription in gastrointestinal cancer cells.
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.
Yamauchi
Akiyo
A
Department of Advanced Biological Sciences for Regeneration, Kotobiken Medical Laboratories, Tohoku University Graduate School of Medicine, Sendai, Japan.
Takahashi
Iwao
I
Takasawa
Shin
S
Nata
Koji
K
Noguchi
Naoya
N
Ikeda
Takayuki
T
Yoshikawa
Takeo
T
Shervani
Nausheen J
NJ
Suzuki
Iwao
I
Uruno
Akira
A
Unno
Michiaki
M
Okamoto
Hiroshi
H
Sugawara
Akira
A
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*
D051847:Lithostathine; D047495:PPAR gamma; C497617:REG1A protein, human; D012333:RNA, Messenger; D045162:Thiazolidinediones