Regulatory mechanisms mediated by peroxisome proliferator‐activated receptor‐β/δ in skin cancer

Abstract

Considerable progress has been made during the past 20 years towards elucidating the role of peroxisome proliferator‐activated receptor‐β/δ (PPARβ/δ) in skin cancer. In 1999, the original notion that PPARβ/δ was involved with epithelial cell function was postulated based on a correlation between PPARβ/δ expression and the induction of messenger RNAs encoding proteins that mediate terminal differentiation in keratinocytes. Subsequent studies definitively revealed that PPARβ/δ could induce terminal differentiation and inhibit proliferation of keratinocytes. Molecular mechanisms have since been discovered to explain how this nuclear receptor can be targeted for preventing and treating skin cancer. This includes the regulation of terminal differentiation, mitotic signaling, endoplasmic reticulum stress, and cellular senescence. Interestingly, the effects of activating PPARβ/δ can preferentially target keratinocytes with genetic mutations associated with skin cancer. This review provides the history and current understanding of how PPARβ/δ can be targeted for both nonmelanoma skin cancer and melanoma and postulates how future approaches that modulate PPARβ/δ signaling may be developed for the prevention and treatment of these diseases.

Activation of Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) in Keratinocytes by Endogenous Fatty Acids

“…That endogenous ligands exist and dynamically modulate gene expression in keratinocytes is strongly supported by previous studies showing that the genetic silencing of Pparb/d in keratinocytes causes alterations in the constitutive expression of hundreds of PPARβ/δ target genes [ 6 ]. Additionally, increasing the basal expression of PPARβ/δ is known to inhibit the size and growth of tumors derived from human skin, neuroblastoma, breast cancer, melanoma, and testicular cancer cell lines implanted in mice, in the absence of exogenous ligands (reviewed in [ 12 , 38 ]). The constitutive, nuclear localization of PPARβ/δ is also relatively high in epithelial cells and PPARβ/δ co-immunoprecipitates with its heterodimerization partner, RXR [ 9 ].…”

“…In contrast, PPARβ/δ is constitutively expressed at a relatively high level in epithelial cells including those in the intestine and skin, in particular in keratinocytes [ 9 , 10 ]. Based on studies using synthetic ligands and transgenic models, it is now recognized that PPARβ/δ has important functional roles in epithelial cells [ 11 , 12 ]. The ligand activation of PPARβ/δ inhibits the proliferation of both mouse primary keratinocytes and human keratinocytes by inducing terminal differentiation through a PPARβ/δ-dependent mechanism [ 12 ].…”

“…Based on studies using synthetic ligands and transgenic models, it is now recognized that PPARβ/δ has important functional roles in epithelial cells [ 11 , 12 ]. The ligand activation of PPARβ/δ inhibits the proliferation of both mouse primary keratinocytes and human keratinocytes by inducing terminal differentiation through a PPARβ/δ-dependent mechanism [ 12 ]. The topical application of a PPARβ/δ ligand is also chemopreventive against chemically induced non-melanoma skin cancer through a PPARβ/δ-dependent mechanism that targets premalignant tumors as a decrease in keratoacanthomas is only noted in ligand-treated wild-type mice but not in Pparb/d -null mice [ 13 , 14 , 15 ].…”

PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming

“…Topical treatment with PPARδ agonists or antagonists should be critically evaluated because data on the role of PPARδ in cancer is controversial [19,85,110]. PPARδ has been shown to inhibit non-melanoma skin cancer by enhancing KC terminal differentiation and senescence, blocking KCs in the G2/M phase of the cell cycle, and inhibiting endoplasmic reticulum stress and specific inflammatory pathways [111][112][113]. However, PPARδ has also been shown to promote KC proliferation via HB-EGF and to contribute to epidermal hyperplasia [38,85].…”