Presenilin mutation suppresses lung tumorigenesis via inhibition of peroxiredoxin 6 activity and expression

Abstract

Some epidemiological studies suggest an inverse correlation between cancer incidence Alzheimer's disease (AD). In this study, we demonstrated experimental evidences for this invrelationship. In the co-expression network analysis using the microarray data and GEO profgene expression omnibus data analysis, we showed that the expression of peroxiredox(PRDX6), a tumor promoting protein was significantly increased in human squamous lung cabut decreased in mutant presenilin 2 (PS2) containing AD patient. We also found in animal mthat mutant PS2 transgenic mice displayed a reduced incidence of spontaneous carcinogen-induced lung tumor development compared to wildtype transgenic mice. Agreed network and GEO profile study, we also revealed that significantly reduced expression of PRand activity of iPLA2 in these animal models. PS2 mutations increased their interaction PRDX6, thereby increasing iPLA2 cleavage via increased γ-secretase leading to loss of PRactivity. However, knockdown or inhibition of γ-secretase abolished the inhibitory effect of mPSs. Moreover, PS2 mutant skin fibroblasts derived from patients with AD showed diminiiPLA2 activity by the elevated γ-secretase activity. Thus, the present data suggest that mutations suppress lung tumor development by inhibiting the iPLA2 activity of PRDX6 γ-secretase cleavage mechanism and may explain the inverse relationship between cancer and incidence.