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Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity

Abstract

Ferroptosis, a form of regulated cell death triggered by lipid peroxidation, was recently identified as an important mechanism in radiotherapy (RT)-mediated tumor suppression and radioresistance, although the exact genetic contexts in which to target ferroptosis in RT remains to be defined. p53 is the most commonly mutated gene in human cancers and a major effector to RT. Here, we identify ferroptosis as a critical mechanism to mediate p53 function in tumor radiosensitivity. Mechanistically, RT-mediated p53 activation antagonizes RT-induced SLC7A11 expression and represses glutathione synthesis, thereby promoting RT-induced lipid peroxidation and ferroptosis. p53 deficiency promotes radioresistance in cancer cells or tumors at least partly through SLC7A11-mediated ferroptosis inhibition. Ferroptosis inducers (FINs) that inhibit SLC7A11 exert significant radiosensitizing effects in tumor organoids and patient-derived xenografts with p53 mutation or deficiency. Finally, we show that RT-induced ferroptosis correlates with p53 activation and better clinical outcomes to RT in cancer patients. Together, our study uncovers a previously unappreciated role of ferroptosis in p53-mediated radiosensitization and suggest using FINs in combination with RT to treat p53-mutant cancers.

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Fig. 1: Ferroptosis is involved in p53-mediated radiosensitization.
Fig. 2: p53 promotes RT-induced ferroptosis partly via antagonizing SLC7A11 induction.
Fig. 3: p53 deficiency contributes to radioresistance partly via SLC7A11-mediated GSH synthesis and ferroptosis inhibition.
Fig. 4: FINs radiosensitize p53-deficient/-mutant cancer cells and tumor organoids.
Fig. 5: Ferroptosis is involved in p53 deficiency-mediated radioresistance and FINs radiosensitize p53-mutant tumors in vivo.
Fig. 6: Ferroptosis induction correlates with p53 activation and better clinical responses to RT in cancer patients.

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Acknowledgements

This research was supported by Institutional Research Fund and RO Strategic Initiatives (ROSI) Boot Walk Seed Award from The University of Texas MD Anderson Cancer Center, KC180131 from Department of Defense Kidney Cancer Research Program, and R01CA181196, R01CA244144, and R01CA247992 from the National Institutes of Health (to BG); P50 CA217685, American Cancer Society, and MD Anderson Moon Shot Program in Ovarian Cancer (to AKS). BG was an Andrew Sabin Family Fellow. PK is supported by CPRIT Research Training Grant (RP170067) and Dr. John J. Kopchick Research Award from The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. This research has also been supported by the National Institutes of Health Cancer Center Support Grant P30CA016672 to The University of Texas MD Anderson Cancer Center.

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GL performed most of the experiments with assistance from YZ, TH, XL, CM, WC, PK, and YY; JL, AKS, TH, and XD provided ovarian cancer organoids; BG designed and supervised the experiments; BG and GL wrote most of the manuscript with assistance from other co-authors; all authors commented on the manuscript.

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Correspondence to Boyi Gan.

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AKS declares the following competing of interests: consulting (Merck, Kiyatec); shareholder (BioPath); and research support (M-Trap). Other authors declare no competing interests.

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Lei, G., Zhang, Y., Hong, T. et al. Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity. Oncogene 40, 3533–3547 (2021). https://doi.org/10.1038/s41388-021-01790-w

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