Distinct molecular mechanisms contribute to the reduction of melanoma growth and tumor pain after systemic and local depletion of alpha‐Synuclein in mice

Abstract

Epidemiological studies show a coincidence between Parkinson's disease (PD) and malignant melanoma. It has been suggested that this relationship is due, at least in part, to modulation of alpha‐Synuclein (αSyn/Snca). αSyn oligomers accumulate in PD, which triggers typical PD symptoms, and in malignant melanoma, which increases the proliferation of tumor cells. In addition, αSyn contributes to non‐motor symptoms of PD, including pain. In this study, we investigated the role of αSyn in melanoma growth and melanoma‐induced pain in a mouse model using systemic and local depletion of αSyn. B16BL6 wild‐type as well as αSyn knock‐down melanoma cells were inoculated into the paws of αSyn knock‐out mice and wild‐type mice, respectively. Tumor growth and tumor‐induced pain hypersensitivity were assessed over a period of 21 days. Molecular mechanisms were analyzed by RT‐PCR and Western Blot in tumors, spinal cord, and sciatic nerve. Our results indicate that both global and local ablation of Snca contribute to reduced tumor growth and to a reduction of tumor‐induced mechanical allodynia, though mechanisms contributing to these effects differ. While injection of wild‐type cells in Snca knock‐out mice strongly increased the immune response in the tumor, local Snca knock‐down decreased autophagy mechanisms and the inflammatory reaction in the tumor. In conclusion, a knockdown of αSyn might constitute a promising approach to inhibiting the progression of melanoma and reducing tumor‐induced pain.

Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma

“…We also speculated that an αSyn gain-of-function in melanoma, where nuclear αSyn is upregulated, could play a potentially protective role against DNA damage. Consistent with this, work by others has shown that αSyn KO human melanoma cells implanted as xenografts in mice exhibit slower growth and increased apoptosis 40 , paired with reduced tumor-induced mechanical allodynia 41 . In addition, WT melanoma cells in αSyn overexpressing mice show increased metastasis 42 , indicating a potentially complex interaction between αSyn within melanoma cells and other tissues in the body.…”

Association between Parkinson’s Disease and Cancer: New Findings and Possible Mediators

“…The accumulation of α-synuclein oligomers has been described as a hallmark of PD. It is also observed in malignant melanoma, where it contributes to the increased proliferation of tumor cells [5,[82][83][84].…”

“…It is well established that accumulation of α-synuclein in PD causes some of the typical signs of this disease, while in malignant melanoma, elevation of α-synuclein increases the proliferation of tumor cells [4,5]. Other factors that may play roles as mediators between cancer and PD pathogenesis are neurotrophic factors, members of the ubiquitin-proteasome system, circulating melatonin, transcription factors, and mutations or polymorphisms in genes involved in the pathogenesis of these diseases.…”