Troglitazone attenuates epidermal growth factor receptor signaling independently of peroxisome proliferator-activated receptor in PC-3 cells.
The role of the peroxisome proliferator-activated receptor-γ (PPARγ) in cell differentiation, cell cycle arrest and apoptosis has attracted increasing attention. Troglitazone (TGZ), a thiazolidinedione ligand of PPARγ, has been recently described as possessing antitumoral properties. We studied the effects of TGZ on proliferation, growth arrest and apoptosis in PC-3 prostate carcinoma cells and its interaction with the signaling pathways of the activated EFG receptor (EGFR). We observed that TGZ, in a dose- and time-dependent manner, inhibited the growth of PC-3 cells independent of PPARγ. In addition, TGZ induced cell cycle arrest and apoptosis. We demonstrated that cell proliferation was stimulated by EFG in a dose- and time-dependent manner and was inhibited by TGZ. The analysis of the main intracellular signaling pathways downstream of the activated EGFR, PI3K-Akt, ERK1/2 cascades and IκBα revealed that TGZ reduced the phosphorylation levels of EGFR and of their downstream inter-mediators which mediate EGF stimulated proliferation. In conclusion, simultaneous targeting of EGFR, PI3K-Akt, ERK1/2 and NF-κB by TGZ could be the molecular mechanism by which TGZ exerts its additive inhibitory effects on PC-3 cell proliferation.
Department of Pathophysiology, Medical College of Qingdao University, Qingdao, P.R. China.
Hai
H
Zhu
Xiaojing
X
Pan
Haiyan
H
Qi
Xuechun
X
Wang
Sichuan
S
Hou
Baojian
B
Han
Zhijun
Z
Liu
Luo
L
Xu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D000970:Antineoplastic Agents; D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D066246:ErbB Receptors; D000077288:Troglitazone