Activation of peroxisome proliferator-activated receptor-gamma induces apoptosis on acute promyelocytic leukemia cells via downregulation of XIAP.
In the present study we investigated the in vitro apoptosis inducing effects of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand ciglitazone (CGZ) on acute promyelocytic leukemia (APL) NB4 cells and its mechanisms of action. The results revealed that CGZ (10-50 micromol/l) inhibited the growth of leukemia NB4 cells and caused apoptosis in a time- and dose-dependent manner. Apoptosis was observed clearly by flow cytometry (FCM) and DNA fragmentation analysis. After treatment by CGZ for 48 h, the percentage of disruption of mitochondrial membrane potential (Deltapsim) was increased in a dose-dependent manner. Western blotting demonstrated the cleavage of caspase-3 zymogen protein and a time-dependent cleavage of poly (ADP-ribose) polymerase (PARP). The results also demonstrated that PPAR-gamma expression was increased concomitantly when apoptosis occurred, and that CGZ-induced apoptosis was inhibited by the PPAR-gamma antagonist GW9662, suggesting a PPAR-gamma dependent signaling pathway in CZG-induced cell death. Moreover, CGZ treatment remarkably downregulated the expression of the X-linked inhibitor of apoptosis protein (XIAP), which was inhibited by GW9662. Of note, a small-molecule XIAP antagonist (1396-12) mimicked the effect of CGZ-induced apoptosis via activation of caspase-3, 7 and 9. The apoptosis-inducing effects by CGZ on fresh APL cells were also found to be remarkable by using FCM and Wright's staining observation. Taken together, our results suggest that downregulation of XIAP and activation of capase-3 play an important role in mediating the PPAR-gamma-dependent cell death induced by CGZ in APL cells. These data provide a novel insight into potential therapeutic strategies for treatment of leukemia.
Liu
Jia-Jun
JJ
Department of Hematology, The Third Hospital of Sun Yat-sen University, Guangzhou, 510630, PR China. jiajunliu2002@yahoo.com.cn
Guo
Yun-Wei
YW
Fang
Zhi-Gang
ZG
Si
Xiao-Ning
XN
Wu
Xiang-Yuan
XY
Liu
Pei-Qing
PQ
Lin
Dong-Jun
DJ
Xiao
Ruo-Zhi
RZ
Xu
Yan
Y
Wang
Chun-Zhi
CZ
Li
Xu-Dong
XD
He
Yi
Y
Huang
Ren-Wei
RW
D000813:Anilides / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D013194:Staining and Labeling; D000077022:Survivin; D045162:Thiazolidinediones / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000814:Aniline Compounds; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; C500895:N-(6-((anilinocarbonyl)amino)-5-((anilinocarbonyl)((1-(4-cyclohexylbutyl)pyrrolidin-2-yl)methyl)amino)hexyl)-N-methyl-N'-phenylurea; D047495:PPAR gamma; D010671:Phenylurea Compounds; D011480:Protease Inhibitors; D000077022:Survivin; D045162:Thiazolidinediones; D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3; C039671:ciglitazone