Functional activation of PPARγ in human upper aerodigestive cancer cell lines

Abstract

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

Association between pioglitazone use and head and neck cancer: Population‐based case‐control study

“…To our knowledge, this is the first epidemiological study using population‐based case‐control methodology to assess the association between pioglitazone use among patients with type 2 DM and the subsequent occurrence of HNC. Our findings contradict previous laboratory research findings, two phase II clinical trials, and a prospective cohort study, which suggested a chemoprotective effect of pioglitazone in oral/head and neck cancers. Notably our study not only showed no protective effect but, on the contrary, shows increased odds of oral cavity and HNC cancer with pioglitazone use.…”

“…PPARγ agonists as a chemoprevention agent for HNC have been established in many laboratory studies . There remains a paucity of human clinical studies, specifically whether PPARγ agonists such as pioglitazone used in patients with type 2 DM could be preventive against HNC .…”

Vanillic acid attenuates obesityviaactivation of the AMPK pathway and thermogenic factorsin vivoandin vitro

“…PPARg, a member of the nuclear receptor family, has been detected both in humans and mice. It acts as one of the key factors regulating glucose metabolism and involves in pathologies of various diseases such as obesity, cancer, and inflammation (46,47). C/EBPa, a member of the basic region leucine zipper family of transcription factors, is involved in adipogenesis of the liver and adipose tissue.…”

Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ‐independent pathway

“…The induction of PPARγ activation on lung cancer cells is associated with decreased expression of anti‐apoptotic regulators Bcl‐2 and Bcl‐w, and activation of extracellular signal regulated kinase (ERK) and p38 mitogen activated protein kinase (p38MAPK) (Giaginis et al, ). PPARγ ligand binding is known to induce PPARγ expression and inhibit proliferation in human oral cancer cells (Wright et al, ). In gastric cancer cells, PPARγ signaling induces tumor growth, and the PPARγ ligand, troglitazone, induces apoptosis via an increase in the level of pro‐apoptotic proteins Bax/Bcl‐2 (Fukuoka et al, ; Liu et al, ).…”

“…protein kinase (p38MAPK) (Giaginis et al, 2012). PPARγ ligand binding is known to induce PPARγ expression and inhibit proliferation in human oral cancer cells (Wright et al, 2017). In gastric cancer cells, PPARγ signaling induces tumor growth, and the PPARγ ligand, troglitazone, induces apoptosis via an increase in the level of proapoptotic proteins Bax/Bcl-2 (Fukuoka et al, 2015;Liu et al, 2013).…”