PPARβ/δ selectively induces differentiation and inhibits cell proliferation

Abstract

Peroxisome proliferator-activated receptor (PPAR) b-null mice exhibit exacerbated epithelial cell proliferation and enhanced sensitivity to skin carcinogenesis, suggesting that ligand activation of PPARb will inhibit keratinocyte proliferation. By using of a highly specific ligand (GW0742) and the PPARb-null mouse model, activation of PPARb was found to selectively induce keratinocyte terminal differentiation and inhibit keratinocyte proliferation. Additionally, GW0742 was found to be anti-inflammatory due to inhibition of myeloperoxidase activity, independent of PPARb. These data suggest that ligand activation of PPARb could be a novel approach to selectively induce differentiation and inhibit cell proliferation, thus representing a new molecular target for the treatment of skin disorders resulting from altered cell proliferation such as psoriasis and cancer.

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

“…Recent literatures suggest that PPAR-b activation induces the terminal differentiation of keratinocytes, coupled with the inhibition of cell proliferation (Schmuth et al, 2004;Kim et al, 2006;Burdick et al, 2006). These studies enable us to hypothesize that PPAR-b possibly has some role in the differentiation of colon cancer, and might affect the cell adhesion, migration and/or invasion that are associated with tumor differentiation.…”

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

“…Anti-inflammatory activity of PPARβ/δ and/or PPARβ/δ ligands has been shown in a number of different models including immune cells, colon epithelium, macrophages, cardiomyocytes, keratinocytes, myoblasts, endothelial cells, nerve tissue and hepatocytes Graham et al 2005;Hollingshead et al 2007b;Jakobsen et al 2006;Kim et al 2006;Nagasawa et al 2006;Peters et al 2000;Polak et al 2005;Rival et al 2002;Schmuth et al 2004;Welch et al 2003;Woo et al 2006). There is also strong evidence that ligand activation of PPARβ/δ promotes terminal differentiation in intestinal epithelium, breast and colon cancer cell lines, trophoblasts and primary keratinocytes (Aung et al 2006;Burdick et al 2007;Kim et al 2006;Marin et al 2006;Nadra et al 2006;Schmuth et al 2004;Tan et al 2001;Varnat et al 2006;Westergaard et al 2001).…”

“…There is also strong evidence that ligand activation of PPARβ/δ promotes terminal differentiation in intestinal epithelium, breast and colon cancer cell lines, trophoblasts and primary keratinocytes (Aung et al 2006;Burdick et al 2007;Kim et al 2006;Marin et al 2006;Nadra et al 2006;Schmuth et al 2004;Tan et al 2001;Varnat et al 2006;Westergaard et al 2001). Evidence from a large number of independent laboratories also shows that cell growth is inhibited by PPARβ/δ and its ligands in colonocytes, keratincytes, cardiomyocytes, fibroblasts, endothelial cells and a variety of cancer cell lines (Ali et al 2005;Aung et al 2006;Burdick et al 2007;Fukumoto et al 2005;Hollingshead et al 2007a;Kim et al 2004;Kim et al 2006;Kim et al 2005;Man et al 2007;Marin et al 2006;Martinasso et al 2006;Matthiessen et al 2005;Michalik et al 2001;Müller-Brüsselbach et al 2007;Nadra et al 2006;Ou et al 2007;Peters et al 2000;Planavila et al 2005;Schmuth et al 2004;Tan et al 2001;Teunissen et al 2007;Varnat et al 2006;Westergaard et al 2001). Given the potential of PPARβ/δ ligands as therapeutic agents, it is of great importance to determine the effect of ligand activation of PPARβ/δ on cell growth in vitro and in vivo.…”

“…Anti-inflammatory activity of PPARβ/δ and/or PPARβ/δ ligands has been shown in a number of different models including immune cells, colon epithelium, macrophages, cardiomyocytes, keratinocytes, myoblasts, endothelial cells, nerve tissue and hepatocytes Graham et al 2005;Hollingshead et al 2007b;Jakobsen et al 2006;Kim et al 2006;Nagasawa et al 2006;Peters et al 2000;Polak et al 2005;Rival et al 2002;Schmuth et al 2004;Welch et al 2003;Woo et al 2006). There is also strong evidence that ligand activation of PPARβ/δ promotes terminal differentiation in intestinal epithelium, breast and colon cancer cell lines, trophoblasts and primary keratinocytes (Aung et al 2006;Burdick et al 2007;Kim et al 2006;Marin et al 2006;Nadra et al 2006;Schmuth et al 2004;Tan et al 2001;Varnat et al 2006;Westergaard et al 2001). Evidence from a large number of independent laboratories also shows that cell growth is inhibited by PPARβ/δ and its ligands in colonocytes, keratincytes, cardiomyocytes, fibroblasts, endothelial cells and a variety of cancer cell lines (Ali et al 2005;Aung et al 2006;Burdick et al 2007;Fukumoto et al 2005;Hollingshead et al 2007a;Kim et al 2004;Kim et al 2006;Kim et al 2005;Man et al 2007;Marin et al 2006;Martinasso et al 2006;Matthiessen et al 2005;Michalik et al 2001;Müller-Brüsselbach et al 2007;Nadra et al 2006;O...…”

Proliferation and cornification during development of the mammalian epidermis

“…During mouse embryonic development, PPAR␣, -␤, and -␥ are first expressed at E13.5. Several in vitro and in vivo studies indicated that PPAR activators accelerate differentiation and cornification in fetal and adult epidermis (Hanley et al, 1998(Hanley et al, , 1999Kim et al, 2005;Komuves et al, 2000a). In addition, in PPAR␣Ϫ/Ϫ mice, cornification is delayed (Schmuth et al, 2002).…”