A research group at Helmholtz Zentrum München, Neuherberg, Germany.
Biomedical research for redox-regulated life and death decisions.
Ferroptosis in degenerative disease and cancer.
Perspective article on ferroptosis in cancer published in Nature Reviews Cancer
In this Perspective article we discuss how metabolic reprogramming in certain tumor entities may contribute to an acquired sensitivity to ferroptosis, thus leaving a potential vulnerability for the efficient treatment of therapy-resistant tumors. As such, we provide an overview of the known mechanisms that regulate sensitivity to ferroptosis in cancer cells and how the modulation of metabolic pathways controlling ferroptosis might reshape the tumor niche, leading to an immunosuppressive microenvironment ultimately promoting tumor expansion (Further reading: José Pedro Friedmann Angeli, Dmitri V Krysko, Marcus Conrad (2019) Ferroptosis at the Crossroads of Cancer-Acquired Drug Resistance and Immune Evasion. Nat Rev Cancer 19, 405-414).
FSP1 is a novel, glutathione-independent ferroptosis suppressor
Using a genetic suppressor screen in cells lacking the key ferroptosis regulator glutathione peroxidase 4 (GPX4), we now report in Nature the discovery of ferroptosis suppressor protein-1 (FSP1; erroneously annotated as apoptosis-inducing factor, mitochondrion-associated 2, AIFM2) as a novel ferroptosis regulator. The underlying mechanism by which FSP1 robustly protects from ferroptosis is that it regenerates extramitochondrial ubiquinone using electrons from NADH and NADPH thereby preventing detrimental lipid peroxidation. Since FSP1 is widely expressed in a number of tumor cell entities, pharmacological targeting of FSP1 may hold the great potential to combat difficult to treat cancers (Doll et al., Nature 2019)(see also “Identification of a ferroptosis suppressor protein allows for new anticancer treatment approach”)
The relevance of selenium utilization by the ferroptosis regulator GPX4 unveiled
Our recent work published in Cell demonstrates that the trace element selenium, discovered 200 years ago by a Swedish scientist, in form of the 21st amino acid selenocysteine was an evolutionary requirement to prevent peroxide-induced inactivation of the ferroptosis regulator glutathione peroxidase 4 (GPX4) (Ingold et al., 2018). Selenium-containing GPX4 thus allows the exploitation of a rich set of polyunsaturated fatty acids in cellular membranes for the development of complex neuronal circuits in mammals and other vertebrates, and the utilization of physiological concentrations of peroxides for redox signaling processes in cells (see also " Selenium protects a specific type of interneurons in the brain").
About Dr. Conrad
The Conrad laboratory investigates the molecular underpinnings about life and death decisions made by cells in normal tissue homeostasis and in disease. While early cell loss and tissue dysfunction causes acute and chronic degenerative diseases such as ischemia/reperfusion injury and neurodegeneration, aberrant killing of premalignant cells is a known factor in tumor development. The main research focus of the Conrad laboratory involves how perturbed cell metabolism, aberrant redox homeostasis and endoplasmic reticulum stress impact on cell death.