Effects of PPARα inhibition in head and neck paraganglioma cells

• Published in: PloS one Vol. 12; no. 6; p. e0178995
• Main Authors: Florio, Rosalba, De Lellis, Laura, di Giacomo, Viviana, Di Marcantonio, Maria Carmela, Cristiano, Loredana, Basile, Mariangela, Verginelli, Fabio, Verzilli, Delfina, Ammazzalorso, Alessandra, Prasad, Sampath Chandra, Cataldi, Amelia, Sanna, Mario, Cimini, Annamaria, Mariani-Costantini, Renato, Mincione, Gabriella, Cama, Alessandro
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08-06-2017; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; Apoptosis; Apoptosis - drug effects; Biology and Life Sciences; Blotting, Western; Breast cancer; Cancer therapies; Caspase; Caspase 3 - metabolism; Caspase 6 - metabolism; Caspase 7 - drug effects; Caspase 7 - metabolism; Caspases - metabolism; Caspases, Initiator - metabolism; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell migration; Cell Survival - drug effects; Cyclin B1; Cyclin D3; Cyclin-dependent kinase 4; Dehydrogenases; Environmental science; Fluorescent Antibody Technique; Genes; GTP-binding protein; Head and neck; Head and Neck Neoplasms - metabolism; Humans; Immunohistochemistry; Immunoreactivity; Inhibition; Kidney cancer; Kinases; Ligands; Medicine and Health Sciences; Melanoma; Metabolism; Morbidity; Mutation; Neck; Neuroendocrine tumors; Otology; Oxazoles - pharmacology; Paraganglioma; Pathology; Peroxisome proliferator-activated receptors; Pharmacy; PPAR alpha - agonists; PPAR alpha - antagonists & inhibitors; PPAR alpha - metabolism; Pyrimidines - pharmacology; Receptor mechanisms; Research and Analysis Methods; Rodents; Signal transduction; Skull; Surgery; Tumor Cells, Cultured; Tumors; Tyrosine - analogs & derivatives; Tyrosine - pharmacology; Wound Healing - drug effects; β-Catenin; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0178995

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.