Background

Important discoveries in the last decades of the 20th century demonstrated that physiological cell death was a regulated process controlled by endogenous biochemical pathways.  These findings profoundly altered our view of animal development and homeostasis, as well as the pathogenesis and treatment of disease: a process once viewed as passive or accidental was now realized to be stereotyped, regulated and an important target for therapy in a range of diseases.  A major goal of biomedical research is to identify and understand the molecular pathways that regulate cell death.

Regulated cell death is frequently equated with 'apoptosis', the first type of regulated cell death to be characterized in detail.  While apoptosis is clearly important for many cell death events in vivo, a growing number of developmentally programmed, homeostatic and cancer therapy-induced cell death events are now recognized to involve non-apoptotic processes. Our lab is pursuing the broad hypothesis that nonapoptotic cell death plays a crucial role in development, homeostasis and anti-cancer therapeutic responses.  We believe that the identification and characterization of non-apoptoptic cell death pathways will yield insights of fundamental biomedical importance.


Project Areas:

I. Ferroptosis

Small molecules can be used to activate or inhibit protein function and thereby discover and study novel cellular phenotypes.  The small molecule named erastin triggers a novel cell death phenotype called ferroptosis.  Ferroptosis requires iron and reactive oxygen species production and is morphologically, biochemically and genetically distinct from apoptosis, programmed necrosis and autophagy-associated death.  This pathway may be selectively activated by erastin and related molecules in certain RAS pathway-mutant tumors and may also be relevant to cell death during glutamate-induced neurodegeneration in the brain.  Our current understanding of the ferroptotic pathway is outlined below.

 

A working model of the ferroptotic pathway.  Erastin somehow inhibits the function of the system xc- cystine/glutamate transporter.  This in turn results in the depletion of intracellular cysteine.  Cysteine is rate-limiting for the synthesis of reduced glutathione (GSH), a key intracellular antioxidant molecule.  Thus, inhibition of system xc- eventually leads to the depletion of GSH and the iron-dependent accumulation of toxic lipid ROS.

A working model of the ferroptotic pathway.  Erastin somehow inhibits the function of the system xc- cystine/glutamate transporter.  This in turn results in the depletion of intracellular cysteine.  Cysteine is rate-limiting for the synthesis of reduced glutathione (GSH), a key intracellular antioxidant molecule.  Thus, inhibition of system xc- eventually leads to the depletion of GSH and the iron-dependent accumulation of toxic lipid ROS.

Specific projects that we will pursue include : 1) determining how modulation of system xc- function triggers ferroptosis, 2) identifying new small molecules that can activate this process, and 3) determining whether ferroptosis is relevant to animal development or applicable to the selective destruction of tumor cells in vivo

II. Ferrostatins

Small molecule inhibitors of cell death are useful as probes to understand biochemical death mechanisms and, potentially, as drugs with which to prevent unwanted cell death clinically.  By screening an in silico-optimized small molecule library for inhibitors of ferroptotic death I found a nanomolar-potent inhibitor of this process that we renamed ferrostatin-1 (Fer-1).  Fer-1 appears to suppress the formation of toxic lipid reactive oxygen species (ROS) that are formed during ferroptosis, as outlined below.  Fer-1 shows promise as an inhibitor of neurodegenerative death, suggesting a role for ferroptosis in this process and potential clinical applications in this area.

Ferrostatin-1 is a small molecule inhibitor of ferroptosis that appears to act by scavenging lipid reactive oxygen species (ROS) from the plasma membrane

Ferrostatin-1 is a small molecule inhibitor of ferroptosis that appears to act by scavenging lipid reactive oxygen species (ROS) from the plasma membrane

Specific projects will involve: 1) the characterization of how ferrostatin-1 is able to specifically prevent ferroptosis, 2) identification of more potent ferrostatin analogs, and, 3) the application of ferrostatin and ferrostatin analogs in various in vivo death models to investigate the role of ferroptosis in these processes. The approaches and techniques deployed here will also be useful for identifying and characterizing new inhibitors of other forms of cell death.