title: 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.
abstract: 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.
authors.affiliation: National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Korea.
authors.forename: Eun Joung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Ki Sook
authors.initials: KS
authors.lastname: Park
authors.forename: Soo Youn
authors.initials: SY
authors.lastname: Chung
authors.forename: Yhun Yhong
authors.initials: YY
authors.lastname: Sheen
authors.forename: Dong Chuol
authors.initials: DC
authors.lastname: Moon
authors.forename: Yeun Sook
authors.initials: YS
authors.lastname: Song
authors.forename: Kyong Soon
authors.initials: KS
authors.lastname: Kim
authors.forename: Sukgil
authors.initials: S
authors.lastname: Song
authors.forename: Yeo Pyo
authors.initials: YP
authors.lastname: Yun
authors.forename: Myung Koo
authors.initials: MK
authors.lastname: Lee
authors.forename: Ki Wan
authors.initials: KW
authors.lastname: Oh
authors.forename: Do Young
authors.initials: DY
authors.lastname: Yoon
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: 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
chemical_list: 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