REG (Regenerating gene) lot 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 PPAR gamma-agonist thiazolidinediones (TZDs) inhibited cell proliferation and REG I alpha protein/mRNA expression in gastrointestinal cancer cells. TZDs inhibited the REG]a gene promoter activity, via its cis-acting element which lacked PPAR response element and could not bind to PPAR,1, in PPAR gamma-expressing gastrointestinal cancer cells. The inhibition was reversed by co-treatment with a specific PPAR gamma-antagonist GW9662. Although TZDs did not inhibit the REG la gene promoter activity in PPAR gamma-non-expressing cells, PPAR gamma overexpression in the cells recovered their inhibitory effect. Taken together, TZDs inhibit REG la gene transcription through a PPAR gamma-dependent pathway. The TZD-induced REG lot 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 I alpha and PPAR gamma. (C) 2008 Elsevier Inc. All rights reserved.