Presenilin-1 Affects Melanoma Cell Behavior in an Amyloid Precursor Protein-Rich, Alzheimer's Disease-like,...

Recent studies report inverse relationships between the incidence of Alzheimer's Disease (AD) and certain malignancies, including melanoma. This has encouraged research into factor(s) in AD that can exert antitumor effects. Presenilin-1 (PS-1) is part of the enzymatic complex that cleaves amyloid precursor protein (APP) into amyloid-beta (Aβ) products that are linked to the neuronal damage seen in AD. PS-1 can also degrade β-catenin and reduce the effectiveness of the "wingless-related integration" (WNT) signaling pathway. Little is known about the relationship between the AD microenvironment, PS-1, and melanoma. We hypothesize that melanoma growth in AD depends on the degree of PS-1-dependent processing of APP into cytotoxic Aβ by melanoma cells. To determine how melanoma reacts to an APP-rich, AD-like microenvironment, PS-1-high (WM1552C) and PS-1-low (C8161) melanoma cells were treated with soluble recombinant human APP (rhAPP). We found that rhAPP treatment significantly reduced cellular activity in WM1552C but not in C8161 cells. Moreover, Aβ products were significantly higher in conditioned media from rhAPP-treated WM1552C compared to controls. Treatment with PS-1 inducing DAPT or PS-1 function inhibiting MRK-560 reversed the effects of rhAPP treatment, respectively in C8161 and WM1552C cells. Furthermore, we found that migration of WM1552C was significantly reduced in the presence of either soluble rhAPP or mouse AD brain tissue, compared to C8161, suggesting that in WM1552C the combination of PS-1 activity and the presence of APP/Aβ in the microenvironment interferes with cell migration. In summary, PS-1 function may predict how melanoma will grow in an APP/Aβ-rich microenvironment, such as AD.