ABSTRACT
Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis1,2. Although other types of necrotic death such as pyroptosis and necroptosis are mediated by active mechanisms of execution3-6, ferroptosis is thought to result from the accumulation of unrepaired cell damage1. Previous studies have suggested that ferroptosis has the ability to spread through cell populations in a wave-like manner, resulting in a distinct spatiotemporal pattern of cell death7,8. Here we investigate the mechanism of ferroptosis execution and discover that ferroptotic cell rupture is mediated by plasma membrane pores, similarly to cell lysis in pyroptosis and necroptosis3,4. We further find that intercellular propagation of death occurs following treatment with some ferroptosis-inducing agents, including erastin2,9 and C' dot nanoparticles8, but not upon direct inhibition of the ferroptosis-inhibiting enzyme glutathione peroxidase 4 (GPX4)10. Propagation of a ferroptosis-inducing signal occurs upstream of cell rupture and involves the spreading of a cell swelling effect through cell populations in a lipid peroxide- and iron-dependent manner.
Subject(s)
Ferroptosis/physiology , Osmosis/physiology , Cell Death/physiology , Cell Line, Tumor , HeLa Cells , Humans , Iron/metabolism , MCF-7 Cells , Necrosis/metabolism , Necrosis/pathology , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , U937 CellsABSTRACT
Cell death can occur through numerous regulated mechanisms that are categorized by their molecular machineries and differing effects on physiology. Apoptosis and necrosis, for example, have opposite effects on tissue inflammation due to their different modes of execution. Another feature that can distinguish different forms of cell death is that they have distinct intrinsic effects on the cell populations in which they occur. For example, a regulated mechanism of necrosis called ferroptosis has the unusual ability to spread between cells in a wave-like manner, thereby eliminating entire cell populations. Here we discuss the ways in which cell death can propagate between cells in normal physiology and disease, as well as the potential exploitation of cell death propagation for cancer therapy.
Subject(s)
Apoptosis/physiology , Entosis/physiology , Ferroptosis/physiology , Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Apoptosis/radiation effects , Bystander Effect/drug effects , Bystander Effect/radiation effects , Entosis/drug effects , Entosis/radiation effects , Ferroptosis/drug effects , Ferroptosis/radiation effects , Humans , Models, Animal , Neoplasms/therapy , Radiotherapy/methodsABSTRACT
The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10â nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Iron/metabolism , Nanoparticles/chemistry , Amino Acids/deficiency , Animals , Cell Death/drug effects , Cell Line, Tumor , Humans , Lysosomes/drug effects , Melanoma , Mice , Mice, SCID , Nanoparticles/therapeutic use , Particle Size , Polyethylene Glycols/chemistry , Quinoxalines/pharmacology , Silicon Dioxide/chemistry , Spiro Compounds/pharmacology , Xenograft Model Antitumor Assays , alpha-MSH/chemistryABSTRACT
The mitotic checkpoint monitors kinetochore-microtubule attachment and prevents anaphase until all kinetochores are stably attached. Checkpoint regulation hinges on the dynamic localization of checkpoint proteins to kinetochores. Unattached, checkpoint-active kinetochores accumulate multiple checkpoint proteins, which are depleted from kinetochores upon stable attachment, allowing checkpoint silencing. Because multiple proteins are recruited simultaneously to unattached kinetochores, it is not known what changes at kinetochores are essential for anaphase promoting complex/cyclosome (APC/C) inhibition. Using chemically induced dimerization to manipulate protein localization with temporal control, we show that recruiting the checkpoint protein Mad1 to metaphase kinetochores is sufficient to reactivate the checkpoint without a concomitant increase in kinetochore levels of Mps1 or BubR1. Furthermore, Mad2 binding is necessary but not sufficient for Mad1 to activate the checkpoint; a conserved C-terminal motif is also required. The results of our checkpoint reactivation assay suggest that Mad1, in addition to converting Mad2 to its active conformation, scaffolds formation of a higher-order mitotic checkpoint complex at kinetochores.
