Ferroptosis: A Novel Form of Cancer Cell Death Induced by the Small Molecule Erastin

In multicellular organisms, proper control of cell death is important for processes such as embryonic development and turnover of adult tissues. Misregulation of cell death contributes to many diseases, including cancer. Human cancers frequently show defects in their ability to initiate or execute apoptotic cell death, making them resistant to many currently available chemotherapeutic agents that target apoptosis. It is therefore of interest to discover alternative cell death programs that may be exploited to specifically eliminate tumor cells. This thesis defines a new form of cancer cell death induced by the small molecule erastin. Erastin is a quinazolinone derivative that was originally identified in a screen for small molecules that are synthetic lethal with the RAS oncogene. In cancer cells with oncogenic RAS-RAF-MEK signaling, erastin induces an iron-dependent, oxidative cell death that lacks hallmarks of classical apoptosis. We refer to this type of cell death as ferroptosis. In this thesis I characterize ferroptosis with respect to other cell death phenotypes and find that it is distinct from previously described cell death paradigms such as apoptosis, autophagic cell death, accidental necrosis, and various forms of programmed necrosis. Ferroptosis involves generation of death-inducing reactive oxygen species (ROS), and I show that this ROS production depends upon activity of NADPH oxidase-1 and pentose phosphate pathway-derived NADPH