Thiazolidinediones induce proliferation of human bronchial epithelial cells through the GPR40 receptor.
Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands that are widely used in type II diabetes treatment. In addition to their ability to improve glucose homeostasis, TZDs possess anti-inflammatory properties and inhibit growth of many cells, particularly cancerous airway epithelial cells. However, the functional effects of PPARgamma ligands on nonmalignant human bronchial epithelial cells have never been investigated. In the present study, we questioned whether PPARgamma ligands may regulate proliferation of human bronchial epithelial cells, and we studied their potential molecular mechanisms. We found that synthetic PPARgamma agonists, rosiglitazone (RGZ) and troglitazone (TGZ), induced proliferation of human bronchial epithelial cells, whereas the endogenous PPARgamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), inhibited cell growth. RGZ and TGZ (10 microM) induced a rapid and transient intracellular Ca(2+) mobilization from thapsigargin-sensitive intracellular stores, whereas 15d-PGJ(2) (5 microM) did not induce any Ca(2+) signal. The PPARgamma antagonist GW-9662 did not inhibit any biological responses, but it reversed the effect of 15d-PGJ(2) on cell growth. Using RT-PCR, we detected mRNA expression of the GPR40 receptor, a G protein-coupled receptor recently identified as a receptor for free fatty acids and TZDs, in human bronchial epithelial cells. Downregulation of GPR40 by small-interfering RNA led to a significant inhibition of TZD-induced Ca(2+) mobilization and proliferation. This study provides evidence for the proliferative effect of anti-diabetic drug TZDs in nonmalignant human bronchial epithelial cells through GPR40 receptor activation, involving an intracellular Ca(2+) signaling pathway.
Service des Maladies Respiratoires, Institut National de la Santé et de la Recherche Médicale Unité 454, Centre Hospitalier Universitaire-Montpellier, France.
Delphine
D
Gras
Pascal
P
Chanez
Valérie
V
Urbach
Isabelle
I
Vachier
Philippe
P
Godard
Caroline
C
Bonnans
D000230:Adenocarcinoma; D000813:Anilides / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology; D020013:Calcium Signaling / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008175:Lung Neoplasms; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D002839:Chromans; C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077288:Troglitazone