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

1. Nat Cell Biol. 2019 May;21(5):579-591. doi: 10.1038/s41556-019-0305-6. Epub 2019 Apr 8. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Chu B(1), Kon N(1), Chen D(1), Li T(1), Liu T(1), Jiang L(1), Song S(1), Tavana O(1), Gu W(2). Author information: (1)Institute for Cancer Genetics, and Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA. (2)Institute for Cancer Genetics, and Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA. wg8@cumc.columbia.edu. 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. DOI: 10.1038/s41556-019-0305-6 PMCID: PMC6624840 PMID: 30962574 [Indexed for MEDLINE]