Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ ligands on nonmalignant human bronchial epithelial cells have never been investigated. In the present study, we questioned whether PPARγ ligands may regulate proliferation of human bronchial epithelial cells, and we studied their potential molecular mechanisms. We found that synthetic PPARγ agonists, rosiglitazone (RGZ) and troglitazone (TGZ), induced proliferation of human bronchial epithelial cells, whereas the endogenous PPARγ ligand, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), inhibited cell growth. RGZ and TGZ (10 μM) induced a rapid and transient intracellular Ca2+ mobilization from thapsigargin-sensitive intracellular stores, whereas 15d-PGJ2 (5 μM) did not induce any Ca2+ signal. The PPARγ antagonist GW-9662 did not inhibit any biological responses, but it reversed the effect of 15d-PGJ2 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 Ca2+ 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 Ca2+ signaling pathway.
PI3K/Akt/JNK/c-Jun Signaling Pathway is a Mediator for Arsenite- Induced Cyclin D1 Expression and Cell Growth in Human Bronchial Epithelial Cells
