The interrelationship of programmed cell deaths and their key proteins: ferroptosis and autophagy in focus
Ferroptosis the recently described form of cell death can be induced by the depletion of GSH or by the inhibition of GPX4 that leads to the generation of ROS and cell death. Ferroptosis was successfully induced by erastin treatment of RAS mutant oncogene cell lines (e.g. HepG2), by glutamate treatment of brain slices or by APAP treatment on primary mice hepatocytes. However the detailed regulation of ferroptosis or its relationship to the other cell death forms such as autophagy, apoptosis, necroptosis) are unknown. Thus we aim at the investigation of these problems by in vitro and in silico methods in our MedInProt project. Ferroptosis will be induced by erastin and acetaminophen treatment. Acetaminophen induces a complex form of cell death, thus the relationship of necroptosis, apoptosis, autophagy and ferroptosis can be easily investigated. It is proposed by our recent results that the stressed (ER and oxidative stress) HepG2 cells try to survive the stress by autophagy, however the permanent stress causes apoptosis. Thus we aim at the investigation of similar process in the case of ferroptosis and autophagy. The earlier successfully applied inductors of autophagy such as resveratrol and EGCG would also be investigated. Since the ferroptosis generated ROS may have any connection to the mitochondrial redox homeostasis we also would like to investigate the effect of erastin and acetaminophen to the mitochondrial ROS signalling pathways. Our results would be implicated into a mathematical model to give a more detailed dynamical description on the ferroptotic regulation network. On the base of our cooperation we can shed light on the time course of ROS induced cell deaths, on the relationships of the key proteins that can play central role in the tumorigenesis and aging.
Orsolya Kapuy - András Szarka