What are the mechanisms of PPAR-gamma-inhibiting pancreatic carcinoma growth?

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the family of ligand-activated nuclear receptor transcription factors, is expressed in many human solid tumors. It was reported that activation of PPAR-gamma can inhibit the growth of pancreatic carcinoma cells, colon cancer cells, gastric cancer cells and liposarcoma cells. Some in vitro studies have recently reported that PPAR-gamma activation has inhibitory effects on the growth of pancreatic carcinoma cells, probably due to its up-regulation of cellular apoptosis and its down-regulation of tumor invasion. However, little attention has previously been paid to PPAR-gamma action on the growth of pancreatic carcinoma in vivo, especially its possible mechanisms. A research team led by Dr. Xing-Peng Wang from China address this question. Their study will be published on January 28, 2009 in the World Journal of Gastroenterology.

In their study, Expressions of PPAR-gamma and retinoid acid receptor (RXR-alpha) were examined by reverse-transcription polymerase chain reaction (RT-PCR) with immunocytochemical staining. Pancreatic carcinoma cells, PANC-1, were treated either with 9-cis-RA, a ligand of RXR-alpha, or with 15-deoxy- delta12,14 prostaglandin J2 (15d-PGJ2), a ligand of PPAR-gamma or both. Antiproliferative effect was evaluated by cell viability using methyltetrazolium (MTT) assay. A pancreatic carcinoma xenograft tumor model of nude mice was established by inoculating PANC-1 cells subcutaneously. Rosiglitazone, a specific ligand of PPAR-gamma, was administered via water drinking in experimental group of nude mice. After 75 d, all mice were sacrificed. Expression of proliferating cell nuclear antigen (PCNA) in tumor tissue was examined with immunohistochemical staining. Expression of vascular endothelial growth factor (VEGF) mRNA in PANC-1 cells, which were treated with 15d-PGJ2 or 9-cis-RA at various concentrations or different duration, was detected by semi-quantitative RT-PCR. Effects of Rosiglitazone on changes of microvascular density (MVD) and VEGF expression were investigated in xenograft tumor tissue. Neovasculature was detected with immunohistochemistry staining labeled with anti-Ⅳ collagen antibody, and indicated by MVD.

RT-PCR and immunocytochemical staining showed that PPAR-gamma and RXR-alpha were expressed in PANC-1 cells at both transcription level and translation level. MTT assay demonstrated that 15d-PGJ2, 9-cis-RA and their combination inhibited the growth of PANC-1 cells in a dose-dependent manner. 9-cis-RA had a combined inhibiting action with 15d-PGJ2 on the growth of pancreatic carcinoma. In vivo studies revealed that Rosiglitazone significantly suppressed the growth of pancreatic carcinoma as compared to control group (P < 0.05), and the growth inhibition rate was 80.7%. Immunohistochemistry study showed that PCNA was down regulated in Rosiglitazone-treated group compared to the control group. 15d-PGJ2, 9-cis-RA and their combination inhibited the expression of VEGF mRNA in PANC-1 cells in a dose- and time-dependent manner. MVD was decreased more significantly in Rosiglitazonetreated mice (10.67 ± 3.07) than in the control group (31.44 ± 6.06) (P < 0.01). VEGF expression in xenograft tumor tissue was also markedly down-regulated in Rosiglitazone-treated mice.

Their results indicated that Activation of PPAR-gamma inhibits the growth of pancreatic carcinoma both in vitro and in vivo. Suppression of tumor angiogenesis by down-regulating the expression of VEGF may be one of the mechanisms by which PPAR-gamma activation inhibits the growth of pancreatic carcinoma.

Source: World Journal of Gastroenterology