Amyloid precursor protein. An Achilles heel to exploit in the treatment of prostate cancer

Background: Epidemiological studies have highlighted an inverse association between cancer and Alzheimers disease (AD), but the mechanisms underlying this association are not currently understood. Amyloid precursor protein (APP) and its cleavage may represent one potential mechanism. Its importance has been heavily researched due to it giving rise to the production of amyloid-beta, a pathological hallmark of AD. APP, however, has not been extensively investigated in cancer. Methods: FFPE prostate tumour and adjacent benign tissue immunohistochemically stained for APP, androgen receptor and the insulin-like growth factor-I receptor (IGF1R). Normal prostate PNT2, androgen sensitive LNCaP and androgen insensitive PC3 in vitro were used to assess the effects of androgen, IGF-I and their inhibitors on APP and its cleavage; changes in protein abundance were measured by western blot; interactions between proteins using co-immunoprecipitation and effects on cell proliferation, apoptosis and cell signalling of APP silenced cells using a BrdU proliferation assay, Muse Cell Analyser and by TMT proteomic analysis respectively. Results: Data showed that APP was upregulated in prostate tumour tissue compared to adjacent benign. Furthermore, in cancer cell models, in contrast to normal prostate epithelial cells, it was observed that APP was critical for prostate cancer cell survival by interacting with androgen and IGF-I signalling pathways. Conclusions: Drugs that target APP have already been developed for AD and our data suggests they offer an exciting opportunity for repurposing in the treatment of prostate cancer.