Abstract
Ferroptosis, a form of regulated cell death caused by lipid peroxidation, was recently identified as a natural tumor suppression mechanism. Here, we show that ionizing radiation (IR) induces ferroptosis in cancer cells. Mechanistically, IR induces not only reactive oxygen species (ROS) but also the expression of ACSL4, a lipid metabolism enzyme required for ferroptosis, resulting in elevated lipid peroxidation and ferroptosis. ACSL4 ablation largely abolishes IR-induced ferroptosis and promotes radioresistance. IR also induces the expression of ferroptosis inhibitors, including SLC7A11 and GPX4, as an adaptive response. IR- or KEAP1 deficiency-induced SLC7A11 expression promotes radioresistance through inhibiting ferroptosis. Inactivating SLC7A11 or GPX4 with ferroptosis inducers (FINs) sensitizes radioresistant cancer cells and xenograft tumors to IR. Furthermore, radiotherapy induces ferroptosis in cancer patients, and increased ferroptosis correlates with better response and longer survival to radiotherapy in cancer patients. Our study reveals a previously unrecognized link between IR and ferroptosis and indicates that further exploration of the combination of radiotherapy and FINs in cancer treatment is warranted.
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Acknowledgements
We thank J. Chen for helpful suggestions and discussions and A. Ninetto from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for manuscript editing. This research was supported by the Andrew Sabin Family Fellow Award, the Sister Institution Network Fund, and a Radiation Oncology Strategic Initiatives (ROSI) Platform Seed Grant from The University of Texas MD Anderson Cancer Center (to B.G.). B.G. is an Andrew Sabin Family Fellow. Y.Z. and P.K. were Scholars at the Center for Cancer Epigenetics at The University of Texas MD Anderson Cancer Center. P.K. is also 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.
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G.L. and Y.Z. performed most of the experiments with assistance from P.K., J.Z., and X.L.; J.A.A., Q.X., Z.L., and H.W. provided patient samples. S.H.L. provided resources for local radiation in animals. B.G. designed the experiments. B.G. and H.W. supervised the study. B.G. wrote most of the manuscript with assistance from other co-authors. All authors commented on the manuscript.
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S.H.L. receives grant funding from Hitachi Chemical Diagnostics, Genentech, Beyond Spring Pharmaceuticals, New River Labs; honorarium from Varian Medical Systems; and serves in Advisory Board for AstraZeneca and Beyond Spring Pharmaceuticals. Other authors declare no competing interests.
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Further information and requests for reagents should be directed to the lead contact, Boyi Gan (bgan@mdanderson.org).
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Lei, G., Zhang, Y., Koppula, P. et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res 30, 146–162 (2020). https://doi.org/10.1038/s41422-019-0263-3
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DOI: https://doi.org/10.1038/s41422-019-0263-3
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