Ferroptosis in Cancer Cell Biology

Abstract

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer.

Keywords: GPX4; cancer; cell death; ferroptosis; inflammation.

Figure 1

Schematic view of the ferroptosis pathway. Ferroptosis pursues upon aberrant build-up of lipid reactive oxygen species (ROS) leading to peroxidation (-OOH) of polyunsaturated fatty acids (PUFAs). Main peroxidation target PUFAs are arachidonic acid (AA) phosphatidylethanolamine (PE) lipid species within cellular membranes leading to membrane destabilisation and rupture. Lipid peroxidation can be triggered by cytosolic redox active iron (Fe²⁺) shuttled into cells bound to transferrin via transferrin receptor (TFRC) endocytosis and endosomal release mediated by divalent metal transporter 1 (DMT1). In the presence of H₂O₂, Fe²⁺ catalyses hydroxyl radical (HO∙) generation in a Fenton reaction, which sets of a radical lipid peroxidation chain reaction. Lipoxygenase (LOX) can equally catalyse lipid peroxidation using Fe²⁺. As a required prerequisite for ferroptosis, Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) generate the pool of AA-containing target lipids. Glutathione peroxidase 4 (GPX4), in turn, hydrolyses lipid peroxides converting them into their respective non-toxic lipid alcohols (-OH). GPX4 requires glutathione (GSH) as a cofactor which upon its oxidation (GSSG) by GPX4 is reduced to GSH by glutathione reductase (GR). GSH synthesis depends on glutamate cysteine ligase (GCL) and glutathione synthetase (GSS) as well as on intracellular cystine shuttled into the cell in exchange for glutamate mediated by system xc^- (SLC3A2 and SCL7A11/xCT). Independently of GSH, ferroptosis suppressor protein 1 (FSP1) generates ubiquinol from ubiquinone which acts as a lipophilic radical trapping agent within membranes thereby protecting from ferroptosis. Oxidative phosphorylation (OXPHOS) and the tricarboxylic acid (TCA) cycle have both been described to be required for ferroptosis triggered by cystine-depletion or system xc^- but not GPX4 inhibition.

Figure 2

Proposed concepts for the influence of ferroptosis on tumour outcome. (A) without raising an immune response, ferroptosis may result in selective and complete killing of tumour cells leading to tumour eradication. (B) if immune-silent, ferroptosis may also merely result in fractional killing of cells within a heterogeneous tumour. Over time, this would lead to selection of ferroptosis resistant clones and their outgrowth and overall promotion of tumours. (C) if ferroptosis were able to raise an M1-type immune response, M1 macrophages would aid T-cell activation and maintain an anti-tumour immune response resulting in tumour eradication. (D) if ferroptosis instead were to raise an M2-type immune response, M2-macrophages would protect tumour cells from T-cell-mediated anti-tumour immune attack, leading to ferroptosis-initiated tumour immune protection and immune escape. Thereby, concept A and C offer a model explaining an anti-tumour effect of ferroptosis, whereas B and D propose model mechanisms for ferroptosis-induced tumour promotion.