Rosiglitazone attenuates insulin-like growth factor 1 receptor survival signaling in PC-3 cells.
PPARgamma, a member of the peroxisome proliferator-activated receptor family, is overexpressed in prostate cancer. Natural and synthetic ligands of PPARgamma via genomic and nongenomic actions promote cell cycle arrest and apoptosis of several prostate cancer cells, in vitro. Insulin-like growth factor 1 (IGF-1) inhibits the adriamycin-induced apoptosis of PC-3 human prostate cancer cells. Therefore, we have analyzed the ability of two PPARgamma ligands,15dPGJ2 and rosiglitazone, a natural and a synthetic PPARgamma ligand, respectively, to increase the adriamycin-induced cytotoxicity of PC-3 cells and to suppress the IGF-1 survival effect on adriamycin-induced apoptosis of PC-3 cells. Our data revealed that both the PPARgamma ligands increased the adriamycin-induced cytostasis of PC-3 cells, however, only rosiglitazone added to the adriamycin-induced apoptosis of PC-3 cells. In addition, rosiglitazone attenuated the type I IGF receptor (IGF-1R) survival signaling on adriamycin-induced apoptosis of PC-3 cells via its nongenomic action on ERK1/2 and AKT phosphorylation. Because the IGF-1R signaling is probably the most important host tissue (bone) metastasis microenvironment-related survival signaling for prostate cancer cells, we conclude that rosiglitazone effects on IGF-1R-mediated activation of ERK1/2 and AKT could have clinical implications for the management of androgen ablation-refractory and chemotherapy-resistant advanced prostate cancer with bone metastasis.
Papageorgiou
Efstathia
E
Department of Experimental Physiology, National and Kapodistrian University of Athens, Goudi-Athens, Greece.
Pitulis
Nea
N
Manoussakis
Menelaos
M
Lembessis
Peter
P
Koutsilieris
Michael
M
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000819:agonists; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism* / Q000502:physiology; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*
C477819:15-deoxyprostaglandin J2; D000970:Antineoplastic Agents; D004338:Drug Combinations; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004317:Doxorubicin; D017526:Receptor, IGF Type 1; D015230:Prostaglandin D2