Peroxisome Proliferator-Activated Receptor γ Regulates E-Cadherin Expression and Inhibits Growth and Invasion of Prostate Cancer

Abstract

Peroxisome proliferator-activated receptor ␥ (PPAR␥) might not be permissive to ligand activation in prostate cancer cells. Association of PPAR␥ with repressing factors or posttranslational modifications in PPAR␥ protein could explain the lack of effect of PPAR␥ ligands in a recent randomized clinical trial. Using cells and prostate cancer xenograft mouse models, we demonstrate in this study that a combination treatment using the PPAR␥ agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy. We show that the combination treatment impairs the bone-invasive potential of prostate cancer cells in mice. In addition, we demonstrate that expression of E-cadherin, a protein involved in the control of cell migration and invasion, is highly up-regulated in the presence of valproic acid and pioglitazone. We show that E-cadherin expression responds only to the combination treatment and not to single PPAR␥ agonists, defining a new class of PPAR␥ target genes. These results open up new therapeutic perspectives in the treatment of prostate cancer.Prostate cancer is the most common form of cancer in men and the second leading cause of cancer deaths. Tumor growth is originally androgen dependent. Androgens exert their effects through activation of the androgen receptor (AR), a member of the hormone nuclear receptor superfamily. In the mature prostatic gland, the AR regulates the expression of genes involved in cell division and proliferation of the epithelial cells (26). The AR is also involved in several other aspects of prostate cellular metabolism, including lipid biosynthesis, and controls the production of specialized secretory proteins with prostate-restricted expression, such as prostate-specific antigen (PSA) (26). When prostate cancer is still hormone dependent, androgen ablation therapy causes regression of the tumor (18), likely through inactivation of the transcription of the AR target genes. However, the durability of this response is inadequate and many men develop recurrent androgen-independent prostate cancer, which has a very poor prognosis (see reference 11 for a review). Other nuclear receptors or locally produced factors that interact with nuclear receptors are likely involved in cell proliferation, differentiation, and apoptosis in the prostate. The peroxisome proliferator-activated receptor ␥ (PPAR␥) is one such factor. PPAR␥ is another member of the hormone nuclear receptor superfamily. As for most of the other members of this family, its activity is regulated by ligands. Prostaglandin J2 and the antidiabetic drugs thiazolidinediones have been determined to be natural and synthetic ligands of PPAR␥, respectively (for a review, see reference 9). PPAR␥ is highly expressed in the adipose tissue and is required for its development through regulation of the expression of adipocyte-specific genes, such as lipoprotein lipase or the fatty acid transport protein aP2. PPAR␥ is expressed in several other tissues in add...

Histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in clear cell sarcoma models

“…PPARG induces terminal differentiation in many cancer cells, including human primary liposarcoma (37) and osteosarcoma (38) cells. PPARG activity is repressed by histone deacetylases (39), and down-regulation of histone deacetylases is an important process during adipocyte differentiation (40). Our study shows that both MS-275 and romidepsin induce significant transcriptional expression of SOX9, MYOD1, and PPARG in all three CCS cell lines, suggesting that in these cells histone deacetylase inhibitors induce early changes also seen in chondrogenic, myogenic, and adipogenic differentiation.…”

Histone deacetylases and cancer

“…HDAC3 and PPARg together bind to the E-cadherin promoter, and repression in this case is mediated by HDAC3. In the presence of the combination of a PPARg agonist and an HDAC inhibitor, HDAC3 and PPARg are no longer bound to the promoter, histone H4 is hyperacetylated at the promoter and E-cadherin is expressed (Annicotte et al, 2006). Since E-cadherin expression often is lost in prostate cancer, combination therapy may reduce metastatic potential of prostate cancer.…”

Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor γ involves angiogenesis inhibition

“…PPARγ plays an important role in insulin sensitization and differentiation of adipocytes, monocytes and macrophages [5] . Activation of PPARγ can also induce growth inhibition in human prostate cancer cells, colon cancer cells, gastric cancer cells [10] , pancreatic cancer cells [12][13][14][15][16][17] and liposarcoma cells [18] . The expression of PPARγ and its role in human pancreatic carcinoma have not been fully elucidated.…”

“…It has been shown that PPARγ gene expression is observed in a variety of tissues, including adipose tissue and tumor tissue. Some in vitro studies have recently reported that PPARγ activation has inhibitory effects on the growth of pancreatic carcinoma cells [13][14][15] , probably due to its up-regulation of cellular apoptosis and its down-regulation of tumor invasion [16][17][18] . However, little attention has previously been paid to PPARγ action on the growth of pancreatic carcinoma in vivo, especially its regulation action on tumor angiogenesis.…”