Inhibition of human chondrosarcoma cell growth via apoptosis by peroxisome proliferator-activated receptor-gamma.
A rare immunohistochemical study using 28 surgical sections of human chondrosarcoma revealed that 67.9% of tumour cells had weak (10-40%) or strong (>40%) positive immunoreaction for peroxisome proliferator-activated receptor-gamma. The expression of peroxisome proliferator-activated receptor-gamma mRNA and protein in human chondrosarcoma cell line OUMS-27 was also determined by reverse transcription-polymerase chain reaction and immunocytochemistry, respectively. Furthermore, the effects of peroxisome proliferator-activated receptor-gamma ligands on cell proliferation and survival were investigated in OUMS-27 cells. Pioglitazone, a selective ligand for peroxisome proliferator-activated receptor-gamma, and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a putative endogenous ligand for peroxisome proliferator-activated receptor-gamma, inhibited the proliferation of OUMS-27 cells in a dose-dependent manner. The mechanism of cytotoxic effects of 15d-PGJ(2) was via apoptosis as shown by DNA fragmentation using TUNEL stain and DNA ladder formation, and by ultrastructural analysis using transmission electron microscopy. Flow-cytometric analysis using annexin-V-fluorescein and propidium iodide detected the early change of apoptosis, as well as necrosis of OUMS-27 cells at 4 h after co-incubation with 15d-PGJ(2). These results suggest that peroxisome proliferator-activated receptor-gamma may play a significant role in the pathogenesis of chondrosarcoma, and peroxisome proliferator-activated receptor-gamma ligands, especially 15d-PGJ(2), may be of therapeutic value in the treatment of human chondrosarcoma.
Nishida
K
K
Department of Orthopaedic Surgery, Faculty of Medicine, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama City, Okayama 700-8558, Japan. knishida@md.okayama-u.ac.jp
Furumatsu
T
T
Takada
I
I
Kawai
A
A
Yoshida
A
A
Kunisada
T
T
Inoue
H
H
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D002813:Chondrosarcoma / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C037112:9-deoxy-delta-9-prostaglandin D2; D015230:Prostaglandin D2; D000077205:Pioglitazone