Ferroptosis is a recently discovered form of cell death that is triggered by the accumulation of oxidatively damaged lipids. These reactive molecules are believed to damage cellular membranes when they build up in cells, which ultimately results in cell death.
Scientists have been very interested in studying whether they can trigger ferroptosis as a method for killing cancer cells. In new research published today in Nature, UC Berkeley scientists and their colleagues identify a new mechanism that protects cancer cells from ferroptosis. This is a promising finding in the field of cancer therapeutics, as scientists may be able to suppress the mechanisms that protect cells from ferroptosis as a strategy to kill cancer cells.
The main pathway that is known to prevent ferroptosis involves a glutathione-dependent peroxidase called GPX4. “A lot of researchers are interested in inhibiting this protective pathway as a way to kill cancer cells,” said co-author James Olzmann, an associate professor in the Department of Nutritional Sciences & Toxicology, “The idea is that if a drug could inhibit GPX4, this could be a way of triggering ferrotopsis and killing cancer cells.”
While there have been some successes with this approach, it is clear that many types of cancer cells are resistant to the inhibition of GPX4, which suggests that there may be additional protective pathways. “Employing a genetic screen, we identified a protein called FSP1 as a powerful suppressor of ferroptosis in cancer,” said Olzmann, “Interestingly, FSP1 acts completely independently of the known glutathione-dependent GPX4 pathway.”
The researchers’ data indicate that FSP1 protects cancer cells by acting on a molecule called CoQ, which in turn functions as a potent antioxidant that prevents the propagation of oxidatively damaged lipids. Generally, CoQ is found in an organelle called the mitochondria, where it participates in the generation of energy during cellular respiration. However, the researchers showed that FSP1 acts on CoQ outside of the mitochondria, an exciting finding since the role of non-mitochondrial CoQ has been a mystery for decades. The results suggest that non-mitochondrial CoQ, together with FSP1, plays a critical role in protecting cellular membranes from damage by preventing lipid oxidation.
“Think of FSP1 like the brakes of a car,” said Olzmann. “If you remove the brakes, the car can move forward. If we inhibit FSP1, then ferroptosis can proceed to kill the cancer cell.”
“Our results demonstrate that FSP1 is broadly involved in cancer resistance to ferrotopsis, and this highlights the need to develop inhibitors of FSP1 as a chemotherapeutic strategy to enhance the effectiveness of ferroptosis-activating therapeutics,” added Olzmann.
Additional UC Berkeley authors on this study include Kirill Bersuker, Joseph Hendricks, Zhipeng Li, Breanna Ford, Melissa A. Roberts, and Daniel K. Nomura from the Department of Nutritional Sciences and Toxicology; Bingqi Tong and Thomas J. Maimon from the Department of Chemistry; and Roberto Zoncu from the Department of Molecular and Cell Biology. A similar but entirely separate study on FSP1 conducted by a group on Germany that yielded the same discovery was co-published in Nature today.
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