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.

High expression and nuclear localization of β-catenin in diffuse large B-cell lymphoma

“…The Wnt/β-catenin pathway is also significantly involved in the progression of numerous types of carcinomas, including leukemia, myeloma (16)(17)(18)(19) and several subtypes of lymphoma (20)(21)(22)(23)(24)(25)(26)(27)(28)(29). It is known that activation of the Wnt/β-catenin pathway could be important for malignancy of DLBCL.…”

“…The Wnt/β-catenin pathway plays an important role in the progression of leukemia, myeloma (16)(17)(18)(19) and several subtypes of lymphoma, such as Epstein-Barr virus (EBV)-positive Burkitt's lymphoma (BL) (20)(21)(22), mantle cell lymphoma (MCL) (23)(24)(25), cutaneous lymphoma (26), extranodal marginal zone lymphoma (27), ALK-positive anaplastic large cell lymphoma (28), small B-cell lymphoma (29) and DLBCL (9,30). Scientists demonstrated that ethacrynic acid (EA) and the antifungal agent ciclopirox olamine (cic) inhibited the Wnt/β-catenin signaling in OPM-2 myeloma and three lymphoma cell lines (OCI-LY8-LAM-53, SU-DHL-4 and Raji) in vitro, leading to apoptosis and a significant decrease in the viability of lymphoma and its cell lines (30).…”

Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention

“…PPAR-γ is also expressed in a number of solid tumors including colon, breast, bladder, lung, and gastric cancers [23] and acts as a tumor suppressor by reducing proliferation and angiogenesis and promoting differentiation. Moreover, TZD class of PPAR-γ agonists have been shown to inhibit the Wnt/β-catenin signaling pathway [45], which functions in the self-renewal capability of cancer stem cells including prostate [46], bladder [47], colon [45], and breast [48] cancer, and also lymphoma [49]. TZD analogs have also recently been identified as potent inhibitors of IGF-1 receptors [50], which are aberrantly activated in several cancers [51].…”

“…The understanding of anti-cancer effects of TZDs still remains elusive and a careful re-examination of its chemistry and pharmacological effect is needed. In addition to anti-cancer effects [45–47,49,52,53], pioglitazone class of TZDs have the potential to attenuate atherosclerosis and reduce the risk of cardiovascular events [42,43]. A recent multi-center clinical trial in non-diabetic insulin resistant patients with a previous history of transient ischemic attack or stroke demonstrated that risk of stroke and myocardial infarction was lower among patients who received pioglitazone than those who received placebo.…”

The role of the Wnt canonical signaling in neurodegenerative diseases

“…Among these, PPARγ is a wellknown β-catenin target gene [64,72] that has shown to exert a strong anti-inflammatory activity by antagonizing the NF-κB-mediated transcription of downstream genes [73]. PPARγ activation in rat hippocampus is correlated with decreased GSK-3β activity [74], suggesting the existence of an interplay between PPARγ and GSK-3β [64,75,76].…”