The Role of PPARβ/δ in Melanoma Metastasis

Abstract

Background: Peroxisome proliferator–activated receptor (PPAR) β/δ, a ligand-activated transcription factor, is involved in diverse biological processes including cell proliferation, cell differentiation, inflammation and energy homeostasis. Besides its well-established roles in metabolic disorders, PPARβ/δ has been linked to carcinogenesis and was reported to inhibit melanoma cell proliferation, anchorage-dependent clonogenicity and ectopic xenograft tumorigenicity. However, PPARβ/δ’s role in tumour progression and metastasis remains controversial. Methods: In the present studies, the consequence of PPARβ/δ inhibition either by global genetic deletion or by a specific PPARβ/δ antagonist, 10h, on malignant transformation of melanoma cells and melanoma metastasis was examined using both in vitro and in vivo models. Results: Our study showed that 10h promotes epithelial-mesenchymal transition (EMT), migration, adhesion, invasion and trans-endothelial migration of mouse melanoma B16/F10 cells. We further demonstrated an increased tumour cell extravasation in the lungs of wild-type mice subjected to 10h treatment and in Pparβ/δ−/− mice in an experimental mouse model of blood-borne pulmonary metastasis by tail vein injection. This observation was further supported by an increased tumour burden in the lungs of Pparβ/δ−/− mice as demonstrated in the same animal model. Conclusion: These results indicated a protective role of PPARβ/δ in melanoma progression and metastasis.

Vascular PPARβ/δ Promotes Tumor Angiogenesis and Progression

“…GW0742 decreased BrdU incorporation and the fraction of PCNA-positive cells significantly, GSK3787 had the opposite effects (Figure 1a-c). These findings are in line with the effects of PPARβ/δ modulation on the proliferation of melanoma cells reported by our group [5] and recently confirmed in a study where a PPARβ/δ antagonist enhanced melanoma progression [28]. To determine whether apoptosis might contribute to the observed effects on cell growth upon GW0742 treatment, we used Annexin V/propidium iodide (PI) labeling to detect apoptotic events followed by fluorescence-activated cell sorting (FACS) analysis.…”

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

“…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 . 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 . By contrast, one published study suggests that ligand activation of PPARβ/δ with GW501516 promotes migration and invasion of a human melanoma cancer cell line .…”

“…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.…”

“…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. 45 By contrast, one published study suggests that ligand activation of PPARβ/δ with GW501516 promotes migration and invasion of a human melanoma cancer cell line. 46 Combined, there is a stronger weight of evidence that targeting PPARβ/δ for melanoma chemoprevention and progression is a promising molecular target, although further studies are needed in more melanoma models to increase the preclinical evidence to support this hypothesis.…”

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).…”