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Treatment with diphenyl–pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death

E. Turriani,Diana F. Lázaro,S. Ryazanov,A. Leonov,A. Giese,M. Schön,M. P. Schön,C. Griesinger,T. Outeiro,D. Arndt-Jovin,D. Becker

Published 2017 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance People with Parkinson’s disease, the second most common neurodegenerative disorder, have a lower risk and decreased incidence of cancer with the one exception being melanoma. The fact that, compared with other malignancies, melanoma occurs more frequently in patients with Parkinson’s disease and vice versa and that there is an association between a history of melanoma and an increased prevalence of prodromal markers of Parkinson’s disease prompted us to explore the possibility of an inverse biological link between these two diseases. The findings of our study suggest that α-synuclein, one of the key regulators in Parkinson’s disease, although toxic to dopaminergic neurons, is protective for advanced melanoma cells. Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson’s disease. Because no evidence could be obtained that genetic factors are the reason for the association between these two diseases, we hypothesized that of the three major Parkinson’s disease-related proteins—α-synuclein, LRRK2, and Parkin—α-synuclein might be a major link. Our data, presented here, demonstrate that α-synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that α-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death. Because this detrimental effect of α-synuclein on neurons can be rescued by the small molecule anle138b, we explored its effect on melanoma cells. We found that treatment with anle138b leads to massive melanoma cell death due to a major dysregulation of autophagy, suggesting that α-synuclein is highly beneficial to advanced melanoma because it ensures that autophagy is maintained at a homeostatic level that promotes and ensures the cell’s survival.

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