Antioxidant Pathways in Cancer Progression

By September 8, 2021

Antioxidant Pathways in Cancer Progression

Tumors experience oxidative stress during all stages of cancer progression due to the generation of reactive oxygen species (ROS) – molecules that react with cellular macromolecules and compromise their function. One major deleterious effect of ROS accumulation is lipid peroxidation, which damages cellular membranes. Excessive accumulation of lipid peroxides disrupts membrane function and leads to a non-apoptotic and iron-dependent form of cell death – ferroptosis. Sensitizing tumors to lipid peroxidation has emerged as a major opportunity for new cancer therapies. Growing evidence suggests lipid peroxides accumulate during radiation therapy, and that mechanisms to suppress ferroptosis result in radioresistance and metastasis.

Execution of ferroptosis requires three factors: ROS, which initiate lipid damage; membrane-incorporated polyunsaturated fatty acids, which are prone to oxidation due to their abundant double bonds; and iron, a transition metal that catalyzes lipid peroxidation. On the other hand, glutathione peroxidase 4 (GPX4) converts lipid peroxides into non-toxic metabolites – thereby allowing cells to resist ferroptosis. Increasing evidence suggests that, in addition to this pathway, tumors rely on alternative mechanisms to counteract lipid peroxidation (Garcia-Bermudez et al. Nature, 2019; Soula et al. Nat Chem Bio, 2020). We hypothesize that cancer cells contain other, uncharacterized mechanisms to suppress lipid peroxidation. Our laboratory aims to identify metabolic genes that promote ferroptosis resistance and test whether disrupting them impairs tumor progression.

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