Ferroptosis, Cellular Metabolism, and Cancer

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Ferroptosis, Cellular Metabolism, and Cancer Summary Programmed cell death plays important roles in normal biology, and its deregulation impacts various human diseases, including cancer. Recent progress has established that in addition to apoptosis, which is the best-established mode of programmed cell death, there are also other forms of programmed cell death. Ferroptosis is a newly emerged programmed necrosis process that is implicated in multiple biological and pathological conditions. However, its precise mechanism and function are not well understood. The overall goal of this proposal is to investigate the molecular basis of ferroptosis and its potential involvement in cancer. This proposal is based on our recent finding that induction of ferroptosis requires the extracellular iron-carrier protein transferrin and the intracellular metabolic process glutaminolysis; and inhibition of glutaminolysis, presumably via blocking ferroptosis, reduces heart injury triggered by ischemia-reperfusion. Because both transferrin and glutaminolysis are crucial for cancer cell viability, our finding that they are involved in the induction of a specific type of cell death is conceptually intriguing and unexpected. Additionally, our preliminary studies indicate that execution of ferroptosis requires active mitochondrial function, further underscoring the intimate relationship between ferroptosis and cellular metabolic and redox machineries. Lastly, we identified the oncogene product MYC, a master regulator of cellular metabolism and mitochondrial function, as a positive regulator of ferroptosis. Based on these preliminary results, in this proposal, we will further study the molecular basis of ferroptosis by focusing on the role and functional interplay of glutaminolysis, iron signaling, and mitochondria, in ferroptosis (Aims-1 & 2). We will also investigate the cancer relevance of ferroptosis. Particularly, as many cancer cells possess MYC overexpression and high levels of glutaminolysis, thus likely to be more susceptible to ferroptosis, can we exploit this property of cancer cells (Achilles heel) to develop ferroptosis-based cancer therapies? Experiments proposed in Aim-3 are expected to provide insights into this cancer-relevant question.