Peroxisome proliferator-activated receptor-gamma activator 15-deoxy-Delta12,14-prostaglandin J2 inhibits neuroblastoma cell growth through induction of apoptosis: association with extracellular signal-regulated kinase signal pathway.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been demonstrated to inhibit growth of several cancer cells. Here, we investigated whether one of the PPAR-gamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15-deoxy-PGJ2) inhibits cell growth of two human neuroblastoma cells (SK-N-SH and SK-N-MC) in a PPAR-gamma-dependent manner. PPAR-gamma was expressed in these cells, and 15-deoxy-PGJ2 increased expression, DNA binding activity, and transcriptional activity of PPAR-gamma. 15-Deoxy-PGJ2 also inhibited cell growth in time- and dose-dependent manners in both cells. Cells were arrested in G2/M phase after 15-deoxy-PGJ2 treatment with concomitant increase in the expression of G2/M phase regulatory protein cyclin B1 but decrease in the expression of cdk2, cdk4, cyclin A, cyclin D1, cyclin E, and cdc25C. Conversely, related to the growth inhibitory effect, 15-deoxy-PGJ2 increased the induction of apoptosis in a dose-dependent manner. Consistent with the induction of apoptosis, 15-deoxy-PGJ2 increased the expression of proapoptotic proteins caspase 3, caspase 9, and Bax but down-regulated antiapoptotic protein Bcl-2. 15-Deoxy-PGJ2 also activated extracellular signal-regulated kinase (ERK) 2. In addition, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor PD98059 (2'-amino-3'-methoxyflavone) decreased 15-deoxy-PGJ2-induced ERK2 activation, and expression of PPAR-gamma, capase-3, and cyclin B1. Moreover, MEK1/2 inhibitor PD98059 significantly prevented against the 15-deoxy-PGJ2-induced cell growth inhibition. We also found that PPAR-gamma antagonist GW9662 (2-chloro-5-nitro-N-phenylbenzamide) reversed the 15-deoxy-PGJ2-induced cell growth inhibition, PPAR-gamma expression, and activation of ERK2. These results demonstrate that 15-deoxy-PGJ2 inhibits growth of human neuroblastoma cells via the induction of apoptosis in a PPAR-gamma-dependent manner through activation of ERK pathway and suggest that 15-deoxy-PGJ2 may have promising application as a therapeutic agent for neuroblastoma.
Kim
Eun Joung
EJ
National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Korea.
Park
Ki Sook
KS
Chung
Soo Youn
SY
Sheen
Yhun Yhong
YY
Moon
Dong Chuol
DC
Song
Yeun Sook
YS
Kim
Kyong Soon
KS
Song
Sukgil
S
Yun
Yeo Pyo
YP
Lee
Myung Koo
MK
Oh
Ki Wan
KW
Yoon
Do Young
DY
Hong
Jin Tae
JT
D000813:Anilides / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004347:Drug Interactions; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009930:Organic Chemicals / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D007155:Immunologic Factors; D016328:NF-kappa B; D009930:Organic Chemicals; C466090:PD 98058; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015230:Prostaglandin D2