title: Inhibition of lymphoma cell proliferation by peroxisomal proliferator-activated receptor-γ ligands via Wnt signaling pathway.
abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in regulating energy balance, glucose and lipid metabolisms and inflammation. PPARγ also exerts multiple anti-cancer effects including tumor growth and angiogenesis inhibition, induction of cell differentiation, and apoptosis. Perturbed Wnt/β-catenin signaling likely plays a key role in tumorigenesis and the interaction between PPARγ and the transcriptional regulator β-catenin maybe important in this process. Phosphorylation of β-catenin by GSK-3β inactivates it and suppresses tumor cell proliferation and self-renewal of tumor stem cells. In combination with Frizzled, Wnt suppresses GSK-3β and causes degradation of β-catenin and activation of many tumor proliferation factors. In the present study, we investigated the effects of PPARγ agonist rosiglitazone (RGZ) and PPARγ antagonist GW9662 on the growth, mitotic cycle, and apoptosis of human lymphoma cell line, Raji cells. We also studied the influence of PPARγ ligands on the expression of β-catenin and GSK-3β in Raji cells to reveal whether Wnt/GSK-3β/β-catenin signaling pathways are involved in PPARγ ligands triggered Raji cell apoptosis. Results showed that both RGZ and GW9662 can inhibit the growth of Raji cells by inducing apoptosis and arresting cell cycle; however, there was no correlation between these effects and expression of PPARγ. Both the PPARγ ligands, RGZ and GW9662, appear to reciprocally regulate the mRNA and protein expressions of GSK-3β, which promotes apoptosis, and of β-catenin, which blocks apoptosis. These results suggest that PPARγ ligands mediate their effects via Wnt/GSK-3β/β-catenin signaling on Raji cell proliferation and survival.
authors.affiliation: Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China. jiajun.l@163.com
authors.forename: Jia-Jun
authors.initials: JJ
authors.lastname: Liu
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Dai
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Pei-Qing
authors.initials: PQ
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Liu
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Fang
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Lin
authors.forename: Ruo-Zhi
authors.initials: RZ
authors.lastname: Xiao
authors.forename: Ren-Wei
authors.initials: RW
authors.lastname: Huang
authors.forename: He-Qing
authors.initials: HQ
authors.lastname: Huang
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008024:Ligands; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000970:Antineoplastic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D051176:beta Catenin; D000077154:Rosiglitazone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3