Effects of PPARα inhibition in head and neck paraganglioma cells

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. PPARa 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 PPARa in HNPGLs was never studied before, we analyzed the potential of modulating PPARa in a unique model of HNPGL cells. We observed an intense immunoreactivity for PPARa in HNPGL tumors, suggesting that this receptor has an important role in HNPGL. A pronounced nuclear expression of PPARa was also confirmed in HNPGL-derived cells. The specific PPARa agonist WY14643 had no effect on HNPGL cell viability, whereas the specific PPARa 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/GSK3 beta/beta-catenin signaling pathway. In conclusion, the PPARa antagonist GW6471 reduces HNPGL cell viability, interfering with cell cycle and inducing apoptosis. The mechanisms affecting HNPGL cell viability involve repression of the PI3K/GSK3 beta/beta-catenin pathway. Therefore, PPARa could represent a novel therapeutic target for HNPGL.