Editor’s Highlight: PPARβ/δ and PPARγ Inhibit Melanoma Tumorigenicity by Modulating Inflammation and Apoptosis

Abstract

Skin tumorigenesis results from DNA damage, increased inflammation, and evasion of apoptosis. The peroxisome proliferator-activated receptors (PPARs) can modulate these mechanisms in non-melanoma skin cancer. However, limited data exists regarding the role of PPARs in melanoma. This study examined the effect of proliferator-activated receptor-β/δ (PPARβ/δ) and PPARγ on cell proliferation, anchorage-dependent clonogenicity, and ectopic xenografts in the UACC903 human melanoma cell line. Stable overexpression of either PPARβ/δ or PPARγ enhanced ligand-induced expression of a PPARβ/δ/PPARγ target gene in UACC903 cell lines as compared with controls. The induction of target gene expression by ligand activation of PPARγ was not altered by overexpression of PPARβ/δ, or vice versa. Stable overexpression of either PPARβ/δ or PPARγ reduced the percentage of cells in the G1 and S phase of the cell cycle, and increased the percentage of cells in the G2/M phase of the cell cycle in UACC903 cell lines as compared with controls. Ligand activation of PPARβ/δ did not further alter the distribution of cells within each phase of the cell cycle. By contrast, ligand activation of PPARγ enhanced these changes in stable UACC903 cells overexpressing PPARγ compared with controls. Stable overexpression of either PPARβ/δ or PPARγ and/or ligand activation of either PPARβ/δ or PPARγ inhibited cell proliferation, and anchorage-dependent clonogenicity of UACC903 cell lines as compared with controls. Further, overexpression of either PPARβ/δ or PPARγ and/or ligand activation of either PPARβ/δ or PPARγ inhibited ectopic xenograft tumorigenicity derived from UACC903 melanoma cells as compared with controls, and this was likely due in part to induction of apoptosis. Results from these studies demonstrate the antitumorigenic effects of both PPARβ/δ and PPARγ and suggest that targeting these receptors may be useful for primary or secondary melanoma chemoprevention.

The Role of PPARβ/δ in Melanoma Metastasis

“…PPARβ/δ was previously shown to be expressed in melanocytes [ 12 ], suggesting a potential physiological role in melanocyte activity and function. Although the activation of PPARβ/δ has no impact on melanocyte proliferation [ 12 ], it significantly inhibits the proliferation of melanoma cells, prevents anchorage-dependent clonogenicity and attenuates ectopic xenograft tumorigenicity [ 13 ]. On the contrary, shRNA-mediated knockdown of PPARβ/δ in a highly malignant mouse melanoma cell line B16-F10 demonstrated reduced lung metastasis and tumour burden [ 9 ].…”

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

“…This inhibition of cell proliferation by ligand activation of PPARβ/δ with either GW0742 or GW501516 was also found in both mouse and human melanoma cell lines and mediated by repression of Wilm's tumor suppressor 1 (WT1) that may, in turn, regulate expression of NESTIN and ZYXIN . These findings are of interest to note because ligand activation of PPARβ/δ with GW0742 and/or overexpression of PPARβ/δ inhibited the growth of ectopic xenografts derived from a human melanoma cell causing a block in cell proliferation at the G2/M phase of the cell cycle and induction of apoptosis as compared to controls . Moreover, because the melanoma cell line used for two of these studies was UACC903, which expresses mutant PTEN and an active AKT3, these results demonstrate that ligand activation and/or overexpression of PPARβ/δ are capable of preventing the negative effects of mutant PTEN and active AKT3, and possibly other mutations known to exist in this melanoma cell line .…”

“…72 Because the latter study applied topical PPARβ/δ ligands postirradiation, the results from this study controlled for the sunscreen effect and provide a better degree of clarity than the former study 68 cell proliferation at the G2/M phase of the cell cycle and induction of apoptosis as compared to controls. 43 Moreover, because the melanoma cell line used for two of these studies 43,73 was UACC903, which expresses mutant PTEN and an active AKT3, these results demonstrate that ligand activation and/or overexpression of PPARβ/ δ are capable of preventing the negative effects of mutant PTEN and active AKT3, and possibly other mutations known to exist in this melanoma cell line. 44,75,76 Consistent with these studies, genetic ablation and pharmacological inhibition of PPARβ/δ demonstrated that PPARβ/δ inhibited epithelial-mesenchymal transition, migration, adhesion, and invasion of a mouse melanoma cell line and that PPARβ/δ prevented metastasis in a syngeneic mouse model of melanoma.…”

“…Reference(s) Activation of PPARβ/δ causes increased terminal differentiation [25][26][27][28] Activation of PPARβ/δ causes inhibition of proliferation [28][29][30][31][32][33][34][35][36] PPARβ/δ modulates bioactivation of chemical carcinogens 37 Ligand activation of PPARβ/δ inhibits non-melanoma skin cancer 32,33,[38][39][40] Inhibition of non-melanoma skin cancer by PPARβ/δ mediated by enhanced terminal differentiation 32,33,39 Inhibition of non-melanoma skin cancer by PPARβ/δ mediated by a block in the G2/M phase of cell cycle 36,40 Inhibition of non-melanoma skin cancer by PPARβ/δ mediated by enhanced senescence 41 Inhibition of non-melanoma skin cancer by PPARβ/δ mediated by inhibition of ER stress 42 Inhibition of non-melanoma skin cancer by PPARβ/δ influenced by inhibition of proinflammatory signaling [29][30][31]38 Ligand activation of PPARβ/δ inhibits melanoma [43][44][45][46] Abbreviations: ER, endoplasmic reticulum; PPARβ/δ, peroxisome proliferator-activated receptor-β/δ. PETERS ET AL.…”

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

“…Indeed, FAs can bind and activate specific nuclear receptors, i.e., PPARs, thus controlling the expression of genes involved in lipid homeostasis, oxidative stress, and inflammation (59,60). Unfortunately, poor knowledge exists on this matter as the only evidence for a role of lipid signaling in melanoma biology comes from two recent papers in which the authors independently remarked an anti-tumor effect of PPARβ/δ and PPARγ in melanoma progression and metastasis (61,62).…”