Effects of PPARα inhibition in head and neck paraganglioma cells

Abstract

Head and neck paragangliomas (HNPGLs) are rare tumors that may cause important morbidity, because of their tendency to infiltrate the skull base. At present, surgery is the only therapeutic option, but radical removal may be difficult or impossible. Thus, effective targets and molecules for HNPGL treatment need to be identified. However, the lack of cellular models for this rare tumor hampers this task. PPARα receptor activation was reported in several tumors and this receptor appears to be a promising therapeutic target in different malignancies. Considering that the role of PPARα in HNPGLs was never studied before, we analyzed the potential of modulating PPARα in a unique model of HNPGL cells. We observed an intense immunoreactivity for PPARα in HNPGL tumors, suggesting that this receptor has an important role in HNPGL. A pronounced nuclear expression of PPARα was also confirmed in HNPGL-derived cells. The specific PPARα agonist WY14643 had no effect on HNPGL cell viability, whereas the specific PPARα antagonist GW6471 reduced HNPGL cell viability and growth by inducing cell cycle arrest and caspase-dependent apoptosis. GW6471 treatment was associated with a marked decrease of CDK4, cyclin D3 and cyclin B1 protein expression, along with an increased expression of p21 in HNPGL cells. Moreover, GW6471 drastically impaired clonogenic activity of HNPGL cells, with a less marked effect on cell migration. Notably, the effects of GW6471 on HNPGL cells were associated with the inhibition of the PI3K/GSK3β/β-catenin signaling pathway. In conclusion, the PPARα antagonist GW6471 reduces HNPGL cell viability, interfering with cell cycle and inducing apoptosis. The mechanisms affecting HNPGL cell viability involve repression of the PI3K/GSK3β/β-catenin pathway. Therefore, PPARα could represent a novel therapeutic target for HNPGL.

The Anticancer Potential of Peroxisome Proliferator‐Activated Receptor Antagonists

“…In addition, GW6471 treatment impacts HNPGL cell migration. The mechanisms affecting HNPGL cell viability involve repression of the PI3K/GSK3β/β‐catenin pathway (Figure ) …”

“… Schematic representation of PPARα antagonist GW6471 antitumor activities. GW6471 affects cancer‐cell viability and migration in tumors overexpressing PPARα by interfering with the expression or activity of key proteins involved in crucial biological processes (see text for details) …”

“…The mechanisms affecting HNPGLc ell viability involve repression of the PI3K/GSK3b/bcatenin pathway (Figure3). [77] AA452 is a N-acylsulfonamide derivative able to revert PPARa activation promoted by the GW7647 agonista tl ow micromolar concentrations. [78] At ime-resolved fluorescencer esonance energy-transfer (TR-FRET) assay shows that AA452 is a competitive PPARa antagonist.…”

“…GW6471 affects cancer-cell viability and migration in tumors overexpressing PPARa by interfering with the expression or activity of key proteins involved in crucial biological processes (see text for details). [66,67,77] Figure 4. Chemical structureso fr epresentative PPARg antagonists.…”

“…[97,99,112] In preclinical studies, antagonizing PPARa is associated with cancer-cell death and ad ecrease in tumor size. [66,67,70,77] Inhibition of PPARg decreases cancer-cellg rowth, prevents tumor in-vasion and metastasis, and blocks tumor formation in several cellular and animal models. [90,[93][94][95] PPARd antagonists repress PPARd-mediated signalingr elatedt oc ancer-cell proliferation and survival through modulation of crucial biological pathways, [107,109] but the role of PPARd in cancer needs to be further elucidated owing to conflicting resultso btained with agonists and antagonists.…”