Project Details
Projekt
Molecular Exploitation of Amyloid Precursor Protein as Novel Ferroptosis Regulator
Applicant
Privatdozent Dr. Vivek Venkataramani
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461705388
Ferroptosis is a newly discovered peculiar form of non-apoptotic cell death, which is morphologically and mechanistically distinct from apoptosis and other forms of non-apoptotic cell death. It is characterized by a rapid iron-dependent excess of lipid hydroperoxides, leading to a loss of membrane integrity in the absence of DNA cleavage. Importantly, ferroptosis is a targetable vulnerability in highly aggressive and “iron-addicted” forms of cancers, like prostate cancer and melanoma. Although iron is central to ferroptosis, little is known about how iron species actually confer this susceptibility. Moreover, it remains elusive what regulatory mechanisms may underlie ferroptosis sensitivity and evasion. We have previously shown that the amyloid precursor protein (APP), a critical iron homeostasis factor that presumably lost its normal function in Alzheimer’s disease (AD), is found overexpressed in several aggressive cancer entities promoting cell viability and tumorigenesis. We have further developed an innovative CE-ICP-MS technique that allows the simultaneous quantification of redox-active Fe2+ and redox-inactive Fe3+ ions, aside from total iron. Via this method, we uncovered that APP suppression results in a robust accumulation of Fe2+-driven lipid peroxidation, sensitizing cancer cells to cell death by ferroptosis. In the proposed work, we will modify our CE-ICP-MS approach to quantitatively distinguish ferritin-bound iron from other iron species, sequentially assess the cellular GSH:GSSG ratio, and characterize further also selenium species (that determine the activity of key ferroptosis blocker GPX4) in the same cell lysate. The overarching goal of this grant application is to assess all indicated parameters in the process of ferroptotic cell death with regard to the presence and absence of APP. Additionally, we will pursue our preliminary observations highlighting that targeting APP triggers a signaling network that regulates iron homeostasis, the response to oxidative stress and the generation of polyunsaturated fatty acids. Utilizing APP-high in vitro and in vivo models of prostate cancer and melanoma, we will comprehensively characterize the downstream targets of APP within the ferroptosis network to provide novel accessible targets for inducing ferroptosis in these tumor cells. Collectively, these experiments will enhance our knowledge of iron metabolism and explore APP-regulatory pathways not previously linked to ferroptosis – efforts that ultimately will pave the way for more effective use of ferroptosis-inducing drugs in cancer therapy.
DFG Programme
Priority Programmes
