The Role of Amyloid Precursor Protein Processing Pathways in Prostate Cancer

Abstract

Aging is a well-established risk factor for both prostate cancer and Alzheimer’s disease
(AD). Paradoxically, epidemiological studies point to an unusual inverse association
between these conditions, implying that the presence of one disease may reduce the risk
of the other. Among the best-characterized molecular pathways in AD is amyloid
precursor protein (APP) processing. Emerging evidence indicates that APP also
contributes to cancer proliferation, invasion, and migration, although the underlying
mechanisms remain unclear. This thesis aimed to investigate the functional role of APP
processing pathways in prostate cancer, with a particular focus on the role of APP in the
actions of key drivers of prostate cancer progression, including dihydrotestosterone
(DHT) and insulin-like growth factor I (IGF-I).
Western blotting data revealed that activation of the androgen-receptor (AR) in LNCaP
cells (AR positive) by DHT promotes non-amyloidogenic processing by increasing the
abundance of APP and its α-secretase enzymes, including A disintegrin and
metalloprotease 10(ADAM10), tumour necrosis factor-alpha converting enzyme (TACE),
and β-site converting enzyme 2 (BACE2), resulting in secretion of soluble APPα, and a
significant increase in cell proliferation. Conversely, inhibiting AR signaling with
enzalutamide (an AR-antagonist) shifts APP processing toward the amyloidogenic
pathway by elevating the β-secretase enzyme, β-site converting enzyme 1 (BACE1), and
increasing soluble APPβ (sAPPβ). Similarly, in AR-negative PC3 cells, activation of the
IGF-1R by exposure to exogenous IGF-I stimulates non-amyloidogenic processing via
upregulation of both APP and BACE2, accompanied by increased secretion of both
sAPPα and sAPPβ. Blocking the IGF-1R with AG1024 (an IGF-I receptor tyrosine kinase
inhibitor) promotes amyloidogenic processing through upregulation of BACE1. Treatment
with sAPPα exerted pro-survival effects in both cell lines, even in the presence of
inhibitors (AG1024 and enzalutamide), as shown by using the cell count & viability assay.
Annexin V results showed that APP silencing induced significant apoptosis in prostate
cancer cells (PC3 and LNCaP), but not in the normal prostate cell line PNT2. Proteomic
analysis further revealed that APP knockdown downregulated proteins involved in cell
cycle regulation and RNA transcription, while upregulating proteins that contribute to cell
death. In summary, this study highlights the oncogenic role of APP and its processing pathways
in prostate cancer, emphasizing the potential role of the non-amyloidogenic product
sAPPα in promoting cancer progression.

Date of Award	17 Mar 2026
Original language	English
Awarding Institution	University of Bristol
Sponsors	Saudi Arabian Cultural Bureau in the UK
Supervisor	Claire M Perks (Supervisor) & Rachel M Barker (Supervisor)