Knocking out alpha-synuclein in melanoma cells downregulates L1CAM and decreases motility

Abstract

The Parkinson’s disease (PD) associated protein, alpha-synuclein (α-syn/SNCA), is highly expressed in aggressive melanomas. The goal of this study was to reveal possible mechanism(s) of α-syn involvement in melanoma pathogenesis. Herein, we asked whether α-syn modulates the expression of the pro-oncogenic adhesion molecules L1CAM and N-cadherin. We used two human melanoma cell lines (SK-MEL-28, SK-MEL-29), SNCA-knockout (KO) clones, and two human SH-SY5Y neuroblastoma cell lines. In the melanoma lines, loss of α-syn expression resulted in significant decreases in the expression of L1CAM and N-cadherin and concomitant significant decreases in motility. On average, there was a 75% reduction in motility in the four SNCA-KOs tested compared to control cells. Strikingly, comparing neuroblastoma SH-SY5Y cells that have no detectable α-syn to SH-SY5Y cells that stably express α-syn (SH/+αS), we found that expressing α-syn increased L1CAM and single-cell motility by 54% and 597%, respectively. The reduction in L1CAM level in SNCA-KO clones was not due to a transcriptional effect, rather we found that L1CAM is more efficiently degraded in the lysosome in SNCA-KO clones than in control cells. We propose that α-syn is pro-survival to melanoma (and possibly neuroblastoma) because it promotes the intracellular trafficking of L1CAM to the plasma membrane.

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

“…We measured an increase in the percentage of cells with micronuclei at baseline in the αSyn KO condition, that was also present 6- and 24-hours post rDNA DSB induction with I-PpoI (Figure 7B). We also measured proliferation, migration, and invasion to determine downstream contributions of αSyn function to these cellular phenotypes, since previous studies have found dysregulation of various growth measurements in αSyn KO cells 40, 59 . SK-Mel28 αSyn KO cells also exhibited impaired proliferation, migration, and invasion capabilities compared to control and αSyn KI-rescue cells (Figure 7C), suggesting that αSyn-mediated rDNA DSB repair is important for cell survival and growth.…”

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].…”