Downregulation of cyclooxygenase-2 expression and activation of caspase-3 are involved in peroxisome proliferator-activated receptor-gamma agonists induced apoptosis in human monocyte leukemia cells in vitro.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a transcription factor important in fat metabolism and PPAR-gamma agonists were recently demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. In the present study, two PPAR-gamma agonists, 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) and a synthetic PPAR-gamma agonist troglitazone (TGZ), were used to investigate activated PPAR-gamma-induced apoptosis on human monocyte leukemia U937 and Mono Mac 6 cells in vitro. The results showed that both U937 and Mono Mac 6 cells demonstrated constitutive activation of COX-2 expression; treatment by 15d-PGJ2 and TGZ could induce apoptosis remarkably in human monocyte leukemia cells by disruption of mitochondrial membrane potential, activation of caspase-3, and causing cleavage of the caspase substrate poly (ADP-ribose) polymerase (PARP). Further studies revealed that treatment by both 15d-PGJ2 and TGZ remarkably downregulated COX-2 expression in these two kind of monocyte leukemia cells as measured by reverse transcriptase PCR (RT-PCR) and Western blot. Furthermore, the expression of Bcl-2 and Bcl-Xl and Mcl-1 was downregulated while Bax expression was upregulated concurrently after the cells were treated by these two agonists, and no variations were found in other Bcl-2 family members such as Bak, Bid, and Bad. Taken together, our results demonstrate for the first time that downregulation of cyclooxygenase-2 expression, disruption of mitochondrial membrane potential, activation of caspase-3, downregulation of Bcl-2, Bcl-Xl, and Mcl-1, and upregulation of Bax are involved in PPAR-gamma agonists-induced apoptosis in these two human monocyte leukemia cells.
Liu
Jia-Jun
JJ
Department of Hematology and Oncology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. jiajunliu2002@yahoo.com.cn
Liu
Pei-Qing
PQ
Lin
Dong-Jun
DJ
Xiao
Ruo-Zhi
RZ
Huang
Min
M
Li
Xu-Dong
XD
He
Yi
Y
Huang
Ren-Wei
RW
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D000077288:Troglitazone; D020298:U937 Cells
D002839:Chromans; D004273:DNA, Neoplasm; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D045162:Thiazolidinediones; C037112:9-deoxy-delta-9-prostaglandin D2; D051546:Cyclooxygenase 2; D053148:Caspase 3; D000077288:Troglitazone; D015230:Prostaglandin D2; D013936:Thymidine