Uncovering potential diagnostic and pathophysiological roles of α-synuclein and DJ-1 in melanoma

Agathe Quesnel; Leya Danielle Martin; Chaimaa Tarzi; Vasileios P Lenis; Nathan Coles; Meez Islam; Claudio Angione; Tiago F Outeiro; Ahmad A Khundakar; Panagiota S Filippou

doi:10.1002/cam4.6900

Uncovering potential diagnostic and pathophysiological roles of α-synuclein and DJ-1 in melanoma

Cancer Med. 2024 Jan 8;13(1):e6900. doi: 10.1002/cam4.6900. Online ahead of print.

Authors

Agathe Quesnel^{1

2}, Leya Danielle Martin^{1

2}, Chaimaa Tarzi^{3

4}, Vasileios P Lenis^{1

2}, Nathan Coles^{1

2}, Meez Islam^{1

2}, Claudio Angione^{2

3

4}, Tiago F Outeiro^{5

6

7

8}, Ahmad A Khundakar^{1

2

5}, Panagiota S Filippou^{1

2}

Affiliations

¹ School of Health & Life Sciences, Teesside University, Middlesbrough, UK.
² National Horizons Centre, Teesside University, Darlington, UK.
³ School of Computing, Engineering & Digital Technologies, Teesside University, Middlesbrough, UK.
⁴ Centre for Digital Innovation, Teesside University, Middlesbrough, UK.
⁵ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁶ Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center, Göttingen, Germany.
⁷ Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
⁸ Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany.

Abstract

Background: Melanoma, the most lethal skin cancer type, occurs more frequently in Parkinson's disease (PD), and PD is more frequent in melanoma patients, suggesting disease mechanisms overlap. α-synuclein, a protein that accumulates in PD brain, and the oncogene DJ-1, which is associated with PD autosomal recessive forms, are both elevated in melanoma cells. Whether this indicates melanoma progression or constitutes a protective response remains unclear. We hereby investigated the molecular mechanisms through which α-synuclein and DJ-1 interact, suggesting novel biomarkers and targets in melanoma.

Methods: The Cancer Genome Atlas (TCGA) expression profiles derived from UCSC Xena were used to obtain α-synuclein and DJ-1 expression and correlated with survival in skin cutaneous melanoma (SKCM). Immunohistochemistry determined the expression in metastatic melanoma lymph nodes. Protein-protein interactions (PPIs) and molecular docking assessed protein binding and affinity with chemotherapeutic drugs. Further validation was performed using in vitro cellular models and ELISA immunoassays.

Results: α-synuclein and DJ-1 were upregulated in primary and metastatic SKCM. Aggregated α-synuclein was selectively detected in metastatic melanoma lymph nodes. α-synuclein overexpression in SK-MEL-28 cells induced the expression of DJ-1, supporting PPI and a positive correlation in melanoma patients. Molecular docking revealed a stable protein complex, with differential binding to chemotherapy drugs such as temozolomide, dacarbazine, and doxorubicin. Parallel reduction of both proteins in temozolomide-treated SK-MEL-28 spheroids suggests drug binding may affect protein interaction and/or stability.

Conclusion: α-synuclein, together with DJ-1, may play a role in melanoma progression and chemosensitivity, constituting novel targets for therapeutic intervention, and possible biomarkers for melanoma.

Keywords: DJ-1; chemotherapeutic drugs; diagnosis; melanoma; molecular docking; α-Synuclein.

Abstract

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