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Mutant p53 reactivators protect breast cancer cells from ferroptosis
Ferroptosis is a novel nonapoptotic form of cell death characterized by iron‐dependent reactive oxygen species‐mediated lipid peroxidation. In several different cell systems, the tumor suppressor p53 can enhance sensitivity to ferroptotic inducers. At least half of all human cancers show loss of fun...
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Published in: | Cell biochemistry and function 2024-06, Vol.42 (4), p.e4036-n/a |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites |
Online Access: | Get full text |
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Summary: | Ferroptosis is a novel nonapoptotic form of cell death characterized by iron‐dependent reactive oxygen species‐mediated lipid peroxidation. In several different cell systems, the tumor suppressor p53 can enhance sensitivity to ferroptotic inducers. At least half of all human cancers show loss of function of p53. Furthermore, many of those tumors express mutant forms of p53 that has lost its wild‐type function. Several groups have designed small molecules that can reactivate the wild‐type function of these missense p53 mutants. We reasoned that p53 reactivators may also enhance sensitivity of certain cancer cells to ferroptosis stimuli. To test this idea we combined a number of different p53 reactivators with small molecule inducers of ferroptosis. In contrast, we observed that several p53 reactivators protected cells from cell death induced by ferroptotic inducers. Surprisingly, this protection still occurred in p53‐null cell lines. We observed that these reactivators were neither free radical scavengers nor ion chelators. One of these p53 reactivator molecules, NSC 59984, reduced expression of GPX4, which is unlikely to explain its ability to reduce sensitivity to ferroptosis. We suggest that these p53 reactivators function via an unknown, p53‐independent manner to suppress ferroptosis.
Significance statement
Previous work led to the development of small molecules capable of reactivating mutant p53 into a wild‐type configuration. We reasoned that since p53 can enhance ferroptotic cell death, then p53 reactivator molecules may synergize with ferroptotic inducers to kill cancer cells. In contrast we observed that p53 reactivators protected from ferroptosis even in cells that do not express p53. This reveals novel cellular activities of these small molecules in modulating the cellular response to redox imbalance. |
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ISSN: | 0263-6484 1099-0844 |
DOI: | 10.1002/cbf.4036 |