Peroxisome Proliferator-Activated Receptor γ Pathway Targeting in Carcinogenesis: Implications for Chemoprevention

Abstract

The peroxisome proliferator-activated receptor (PPAR) g is one member of the nuclear receptor superfamily that contains in excess of 80 described receptors. PPARg activators are a diverse group of agents that range from endogenous fatty acids or derivatives (linolenic, linoleic, and 15-deoxy-D 12,14 -prostaglandin J 2 ) to Food and Drug Administration-approved thiazolidinedione drugs [pioglitazone (Actos) and rosiglitazone (Avandia)] for the treatment of diabetes. Once activated, PPARg will preferentially bind with retinoid X receptor a and signal antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for down-regulation of carcinogenesis. Although PPAR-g activators show many anticancer effects on cell lines, their advancement into human advanced cancer clinical trials has met with limited success. This article will review translational findings in PPARg activation and targeting in carcinogenesis prevention as they relate to the potential use of PPARg activators clinically as cancer chemoprevention strategies.

Chemopreventive Effects of Pioglitazone on Chemically Induced Lung Carcinogenesis in Mice

“…23). In our studies, proapoptotic effects were demonstrable in both p53 wt/wt and p53 wt/Ala135Val mouse models and in the SCC model.…”

“…G0S2 has been found to be frequently methylated in SCC of the lung (41), suggesting that G0S2 may have tumorsuppressive functions in the context of lung SCC. Additional mechanisms, such as induction of differentiation (24,25,27), inhibition of invasion, and inhibition of angiogenesis, may also be significant (23).…”

“…Activation of PPARγ inhibits multiple aspects of the malignant phenotype, including proliferation, invasiveness, and metastasis (reviewed recently by refs. 22,23). PPARγ ligands have been shown to inhibit the growth of multiple different cancer cell lines in vitro and in xenograft animal model systems, including cell lines derived from non-small cell lung cancer (NSCLC; refs.…”

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

“…LXR alpha (LXRA, NR1H3) was significantly underexpressed in ACCs in three studies (Giordano et al, 2009;To¨mbo¨l et al, 2009;de Reynie`s et al, 2009) that may be related to the already described loss of chr11p11 (Figure 3; Supplementary Table 3). PPAR-g (PPARG) regulates expression of genes involved in glucose and lipid homeostasis and is implicated in the pathogenesis of several tumours (Ondrey, 2009). PPARG is expressed in normal adrenals, benign and malignant ACTs (Betz et al, 2005), and in the NCI-H295 cell line (Ferruzzi et al, 2005).…”

Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor γ-independent regulation of nucleophosmin

“…5 Despite the suggestions that TZD might favor cancer remission, there are conflicting data on whether PPARc activation promote or suppress tumorigenesis when applied in animal model of cancer. 6 Studies in colon and breast carcinogenesis have shown that TZDdependent activation of PPARc leads to an increase of tumor formation. 7,8 In addition, PPARc is overexpressed in many epithelial tumor cells and regulates the production of hepatocyte growth factor which can favor tumor growth, suggesting that this nuclear receptor might represent a prosurvival factor.…”