PPARγ ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21WAF1/Cip1 pathway

Abstract

P eroxisome proliferator-activated receptor-␥ (PPAR␥)is a member of the nuclear hormone receptor superfamily, which includes receptors for steroids, thyroid hormone, and retinoic acid. 1 PPAR␥ is highly expressed in adipose tissue and plays an important role in adipogenesis and insulin sensitization. 2-6 PPAR␥ ligands, some of which are clinically used as a new class of antidiabetic drugs, have been shown to regulate cell proliferation and differentiation in various tumor cells. 7 PPAR␥ is expressed in several human cancers, including hepatocellular carcinoma, and PPAR␥ ligands can inhibit the growth of these tumor cells. 7-9 These observations as well as the genetic studies in human cancer specimens strongly suggest an antineoplastic and prodifferentiation effect of PPAR␥, in spite of the inconclusive findings from the animal colon tumor model. 7 To date, the biological role of PPAR␥ in cholangiocarcinoma growth has not been investigated.Recent studies have shown that PPAR␥ ligands inhibit cell cycle progression at the G1/S checkpoint, and this effect may be mediated through several mechanisms, including: (1) inhibiting the binding of E2F/DP heterodimers to its target genes by downregulation of PP2A Abbreviations: PPAR␥, peroxisome proliferator-activated receptor-␥; PPRE, peroxisome proliferator response element; CDK, cyclin-dependent kinase; SSM, serum-supplemented medium; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G. From the

Cyclooxygenase-2 Promotes Human Cholangiocarcinoma Growth

“…The expression of p27 is increased in lung cancer cells after treatment with the COX-2 inhibitor NS-398, suggesting that cdk inhibitors may be potential targets for COX-2 inhibitor-mediated inhibition of tumor growth (67). The cdk inhibitors p21 waf1/cip1 , p27 kip1 , and GADD45 have been shown recently to play a critical role in the regulation of human intrahepatic cholangiocarcinoma growth (57)(58)(59)(60)68). For example, decreased expression of p21 waf1/cip1 and p27 kip1 in human cholangiocarcinoma tissue is associated with poor patient survival (57-60); induction of GADD45 is an important mechanism for agonist-induced G 2 -M phase arrest in human cholangiocarcinoma cells (68).…”

“…The cdk inhibitors p21 waf1/cip1 , p27 kip1 , and GADD45 have been shown recently to play a critical role in the regulation of human intrahepatic cholangiocarcinoma growth (57)(58)(59)(60)68). For example, decreased expression of p21 waf1/cip1 and p27 kip1 in human cholangiocarcinoma tissue is associated with poor patient survival (57-60); induction of GADD45 is an important mechanism for agonist-induced G 2 -M phase arrest in human cholangiocarcinoma cells (68). In the present study, we found that celecoxib treatment significantly increased the p21 waf1/cip1 and p27 kip1 protein level in a doseand time-dependent fashion in human cholangiocarcinoma cells, whereas the protein levels of p18 ink4c and GADD45 were not altered.…”

Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor γ and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice

“…AIB3 is a transcriptional coactivator for PPAR␥, RAR, and RXR. The ligands of these nuclear receptors have been shown to inhibit cancer cell growth, induce cell apoptosis, promote terminal differentiation of breast cancer cells, and even reverse malignant changes of certain cancers (43,(55)(56)(57). Haploid inactivation of PPAR␥ alleles promotes colon carcinogenesis in mice treated with PPAR␥ ligand (48).…”

Role of Nuclear Receptors in the Biliary Epithelium

“…The effect of PPAR-γ was linked to its ability to bind to nuclear Smad2/3, thus inhibiting Smad2/3 transcriptional activity [55]. However PPAR-γ ligands were also shown to inhibit the growth of biliary epithelial cancer cells by inducing the expression of p53 [56]. PPAR-γ activation did not result in increased p53 mRNA levels, but was shown to induce an accumulation of the p53 protein [56].…”