Functional activation of PPARgamma in human upper aerodigestive cancer cell lines.

Upper aerodigestive cancer is an aggressive malignancy with relatively stagnant long-term survival rates over 20 yr. Recent studies have demonstrated that exploitation of PPARgamma pathways may be a novel therapy for cancer and its prevention. We tested whether PPARgamma is expressed and inducible in aerodigestive carcinoma cells and whether it is present in human upper aerodigestive tumors. Human oral cancer CA-9-22 and NA cell lines were treated with the PPAR activators eicosatetraynoic acid (ETYA), 15-deoxy-delta- 12,14-prostaglandin J2 (PG-J2), and the thiazolidinedione, ciglitazone, and evaluated for their ability to functionally activate PPARgamma luciferase reporter gene constructs. Cellular proliferation and clonogenic potential after PPARgamma ligand treatment were also evaluated. Aerodigestive cancer specimens and normal tissues were evaluated for PPARgamma expression on gene expression profiling and immunoblotting. Functional activation of PPARgamma reporter gene constructs and increases in PPARgamma protein were confirmed in the nuclear compartment after PPARgamma ligand treatment. Significant decreases in cell proliferation and clonogenic potential resulted from treatment. Lipid accumulation was induced by PPARgamma activator treatment. 75% of tumor specimens and 100% of normal control tissues expressed PPARgamma RNA, and PPARgamma protein was confirmed in 66% of tumor specimens analyzed by immunoblotting. We conclude PPARgamma can be functionally activated in upper aerodigestive cancer and that its activation downregulates several features of the neoplastic phenotype. PPARgamma expression in human upper aerodigestive tract tumors and normal cells potentially legitimizes it as a novel intervention target in this disease. (c) 2016 Wiley Periodicals, Inc.