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ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway

Open access
Chu, Bo, Kon, Ning, Chen, Delin, Li, Tongyuan, Liu, Tong, Jiang, Le, Song, Shujuan, Tavana, Omid, Gu, Wei·2019·Nature Cell Biology

Abstract

It is well established that ferroptosis is primarily controlled by glutathione peroxidase 4 (GPX4). Surprisingly, we observed that p53 activation modulates ferroptotic responses without apparent effects on GPX4 function. Instead, ALOX12 inactivation diminishes p53-mediated ferroptosis induced by reactive oxygen species stress and abrogates p53-dependent inhibition of tumour growth in xenograft models, suggesting that ALOX12 is critical for p53-mediated ferroptosis. The ALOX12 gene resides on human chromosome 17p13.1, a hotspot of monoallelic deletion in human cancers. Loss of one Alox12 allele is sufficient to accelerate tumorigenesis in Eμ-Myc lymphoma models. Moreover, ALOX12 missense mutations from human cancers abrogate its ability to oxygenate polyunsaturated fatty acids and to induce p53-mediated ferroptosis. Notably, ALOX12 is dispensable for ferroptosis induced by erastin or GPX4 inhibitors; conversely, ACSL4 is required for ferroptosis upon GPX4 inhibition but dispensable for p53-mediated ferroptosis. Thus, our study identifies an ALOX12-mediated, ACSL4-independent ferroptosis pathway that is critical for p53-dependent tumour suppression. Chu et al. identify the lipoxygenase ALOX12 as essential for p53-dependent ferroptosis in a pathway independent of GPX4. Monoallelic deletion of Alox12 abrogates p53-mediated suppression in a model of Eµ-Myc-driven lymphoma.

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Metadata

Authors
Chu, B., Kon, N., Chen, D., Li, T., Liu, T., Jiang, L., Song, S., Tavana, O., & Gu, W.
Venue
Nature Cell Biology
Published
2019-04-08
Volume
21
Issue
5
Pages
579-591
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
OpenAlex
W2929538902
Cited by
882
References
11
FWCI
51.06
Type
journal article
Language
en
Open access
green

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CoChat. (2026). Citation check: ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. https://app.cochat.ai/papers/10.1038/s41556-019-0305-6
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Chu, B., Kon, N., Chen, D., Li, T., Liu, T., Jiang, L., Song, S., Tavana, O., & Gu, W. (2019). ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nature Cell Biology. https://doi.org/10.1038/s41556-019-0305-6

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