PPAR-γ ligand promotes the growth of APC-mutated HT-29 human colon cancer cells in vitro and in vivo

Abstract

PPAR-gamma has been known to induce suppression, differentiation and reversal of malignant changes in colon cancer in vitro. However, there are several reports that PPAR-gamma ligands enhance colon polyp development in APCmin mice in vivo. These contradictory results have not yet been thoroughly explained. To explain the contradictory results, we analyzed the effects of different concentrations of the PPAR-gamma agonist, 15-deoxy-D12, 14-prostaglandin (15-d Delta PGJ2) and pioglitazone, on APC gene-mutated colon cancer cell lines (HT-29). We measured cell growth and suppression by cell count and MTT assay and analyzed the expression of beta-catenin and c-Myc protein by Western blot. In addition, we inoculated HT-29 cells into APCmin mice to compare tumor size. High concentrations (10-100 microM/L 15-d Delta PGJ2 and pioglitazone) of PPAR-gamma ligand suppressed growth, while low concentrations (0.01-1 microM/L 15-d Delta PGJ2 and pioglitazone) of PPAR-gamma ligand promoted growth. In particular, the effects of 0.1 microM/L 15-d Delta PGJ2 and pioglitazone on cell growth were statistically significant (P = 0.003, P = 0.001, respectively). Tumor growth was associated with an increase in beta-catenin and c-Myc expression. The growth of xenograft tumors was greater in PPAR-gamma ligand-treated mice than in control mice (control vs day 14: P = 0.024, control vs day 28: P = 0.007). The expression of beta-catenin and c-Myc protein were also elevated in PPAR-gamma-treated mouse tissues. PPAR-gamma ligand can promote the growth of APC-mutated HT-29 colon cancer cells in vitro and in vivo. In addition, the tumor promoting effect seems to be associated with an increase in beta-catenin and c-Myc expression. We think that well-controlled clinical trials should be conducted to confirm our results and to verify clinical applications.

Bean (Phaseolus vulgaris L.) polysaccharides modulate gene expression in human colon cancer cells (HT-29)

“…The down regulation of NF-jb1, and suppression of TNF and IL6 after 24 h of FE-hgf-LC 50 treatment (1.3-and 1.8-fold, respectively), suggests its potential role in inhibiting the inflammatory process. The partial suppression of NF-jb1 activity by butyrate with immune suppressing and anti-inflammatory properties produced during fibre colonic fermentation (Ahmed et al, 2000; Millard The c-myc gene was down regulated 5.4-fold suggesting HT-29 cell differentiation that could lead to general chromatin reorganization (Kuroda et al, 2004), or potential induction of enterocytic differentiation by sodium butyrate (NaBu) (Choi, Kim, & Seo, 2008;Kovaříková, Pachernik, Hofmanová, Zadak, & Kozubík, 2000).…”

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

“…Similarly, rosiglitazone was shown to inhibit mouse lung tumor cell growth and metastasis in vivo through direct and indirect anti-angiogenic effects [82] . Although the above studies reveal important anticancer effects for PPARγ ligands, it is important to note that PPARγ signaling has also been associated with tumor promoter activity in some cancer cells such as colon and breast, and that this effect was linked to increased β-catenin, c-Myc, Angptl4 and Wnt 5 expression [83][84][85] (Table 1). PPARγ ligands enhanced 7,12-dimethylbenz(a)anthracene-induced rat mammary adenocarcinoma [86] and promoted colonic tumor growth in Apc Min mice fed a high-fat diet [87] .…”

The fermented non-digestible fraction of common bean (Phaseolus vulgaris L.) triggers cell cycle arrest and apoptosis in human colon adenocarcinoma cells

“…The HT-29 cell line, derived from human colon adenocarcinoma, was established in 1975 (Fogh and Trempe 1975). Genetically, HT-29 cells present typical changes in colorectal tumors, such as APC, K-ras and p53 mutations and the consequent loss of their function, as well as amplification of c-myc (Rodrigues et al 1990;Choi et al 2008;Zhang et al 2009;Wu et al 2010) and a phenotype of chromosomal instability and aneuploidy. This cell line has been used as a model to investigate the mechanism by which some protective compounds sensitize HT-29 cells to control of proliferation and apoptosis (Beyer-Sehlmeyer et al 2003;Daly et al 2005;Campos-Vega et al 2010).…”