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

Abstract

AbstractEpidemiological 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.