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Peroxisome proliferator-activated receptor α (PPARα) contributes to control of melanogenesis in B16 F10 melanoma cells

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Abstract

Recent studies revealed the cooperation between peroxisome proliferator-activated receptor gamma (PPARγ) and α-MSH signaling, which results in enhanced melanogenesis in melanocytes and melanoma cells. However, the agonists of PPARα, such as fenofibrate, exert depigmenting effect. Therefore, we aimed to check how the PPARα expression level affects the antimelanogenic activity of fenofibrate and whether PPARα modulates melanogenesis independently of its agonist. To answer these questions, we used three B16 F10-derived cell lines, which varied in the PPARα expression level and were developed by stable transfection with plasmids driving shRNA-based PPARα silencing or overexpression of PPARα-emerald GFP fusion protein. Melanin contents were assessed with electron paramagnetic resonance spectroscopy along with color component image analysis—a novel approach to pigment content characteristics in melanoma cells. B16 F10 wt and Ctrl shRNA lines showed intermediate pigmentation, whereas the pigmentation of the B16 F10-derived cell lines was inversely correlated with the PPARα expression level. We observed that cells overexpressing PPARα were almost amelanotic and cells with reduced PPARα protein level were heavily melanized. Furthermore, fenofibrate down-regulated the melanogenic apparatus (MITF, tyrosinase, and tyrosinase-related proteins) in the cells with the regular PPARα expression level resulting in their visibly lower total melanin content in all the cell lines. From these observations, we conclude that fenofibrate works as a strong depigmenting agent, which acts independently of PPARα, but in an additive fashion. Our results also indicate that alterations in PGC-1a acetylation and expression level might contribute to the regulation of melanogenesis by PPARα and fenofibrate.

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Abbreviations

AMPK:

AMP-dependent protein kinase

ASP:

Agouti signaling protein

DOPA:

Dihydroxyphenylalanine

DHICA:

5,6-Dihydroxyindole-2-carboxylic acid

EPR:

Electron paramagnetic resonance (called also ESR—electron spin resonance)

MITF:

Microphthalmia-associated transcription factor

MSH:

Melanocyte-stimulating hormone

PBS:

Phosphate-buffered saline

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha

POMC:

Proopiomelanocortin

PPAR:

Peroxisome proliferator-activated receptor

PPRE:

PPAR response element

RAR:

All trans-retinoic acid receptor

ROR:

Retinoic acid-related orphan receptor

RXR:

Retinoid X receptor

Trp1, Trp2:

Tyrosinase-related protein 1, 2

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Acknowledgements

This work has been supported by the Foundation for Polish Science grant to MG in the POMOST program co-financed by the European Union within European Regional Development Fund. We would like to thank Dr. Heinz Arnheiter from the National Institute of Neurological Disorders and Stroke, USA for excellent anti-MITF antibody, and Dr. Vincent Hearing from the National Cancer Institute, USA for αPEP7 and αPEP8 antibodies. The Faculty of Biochemistry, Biophysics, and Biotechnology of Jagiellonian University is a partner of the Leading National Research Center (KNOW) supported by the Polish Ministry of Science and Higher Education. The paper was partially supported from this fund (PMP, Grant KNOW 35p/10/2015).

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  1. Department of Food Biotechnology, Faculty of Food Technology, University of Agriculture, ul. Balicka 122, 30-149, Kraków, Poland

    Maja Grabacka, Michel Malinowski & Katarzyna Wojcik

  2. Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387, Kraków, Poland

    Justyna Wieczorek, Dominika Michalczyk-Wetula, Norbert Wolan & Przemyslaw M. Plonka

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  1. Maja Grabacka
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Correspondence to Maja Grabacka.

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Grabacka, M., Wieczorek, J., Michalczyk-Wetula, D. et al. Peroxisome proliferator-activated receptor α (PPARα) contributes to control of melanogenesis in B16 F10 melanoma cells. Arch Dermatol Res 309, 141–157 (2017). https://doi.org/10.1007/s00403-016-1711-2

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