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

By Bo Chu, N. Kon, Delin Chen, Tongyuan Li, Tong Liu, Le Jiang, Shujuan Song, O. Tavana, W. Gu. Nature Cell Biology, 2019

792 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/c00087b39d66324738c744a936956789e32a640b

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In Molecular Biology

1. D. Tang
2. R. Kang
3. Guido Kroemer
4. Xin Chen
5. Brent R. Stockwell
6. Xuejun Jiang
7. Yongsheng Li
8. Dingshan Li

In Pulmonary and Respiratory Medicine

1. D. Tang
2. R. Kang
3. Guido Kroemer
4. Brent R. Stockwell
5. Xin Chen
6. Xuejun Jiang
7. Qing-zhang Tuo
8. P. Lei

Citations in the corpus

• Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “It has been progressively recognized that several oncogenic pathways are closely associated with ferroptosis.100 For example, most KRAS mutation-driven pancreatic cancers are sensitive to ferroptosis activators, Erastin.101,102 Furthermore, new evidence suggests that as cancer suppressor gene, p53 i”
• Ferroptosis in infection, inflammation, and immunity (2021, background): “Finally, several lipid-peroxidizing enzymes (e.g., lipoxygenases [ALOXs]; Chu et al., 2019; Kuang et al., 2021; Li et al., 2021; Wenzel et al., 2017; Yang et al., 2016; and cytochrome P450 oxidoreductase [POR]; Yan et al., 2021; Zou et al., 2020b) catalyze the oxidation of PUFA to drive ferroptosis.”
• Regulated cell death (RCD) in cancer: key pathways and targeted therapies (2022, background): “ferroptosis.(369) Whether this process needs the participation of other members of the ACSL family remains to be studied.”
• Targeting p53 pathways: mechanisms, structures and advances in therapy (2023, background): “ALOX12 was also reported to be required for p53mediated ferroptosis.(131) Moreover, p53 promotes ferroptosis through modulation of GLS2, PTGS2, FDXR and noncoding RNAs.”
• Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “13,150,151 While the acetylation-defective mutant p53 3KR (K117R, K161R, K162R) loses its conventional functions of promoting cell-cycle arrest, apoptosis, and senescence, it still retains its tumor-suppressive ability by promoting ferroptosis.”
• Emerging mechanisms and disease relevance of ferroptosis (2020, background): “Moreover, ferroptosis can occur in an ACSL4-independent manner, since ACSL4 is dispensable for the ferroptosis induced by the p53–ALOX12 axis [72].”
• Ferroptosis: mechanisms and links with diseases (2021, background): “For tumor protein 53 (p53)-dependent cancer suppression,12-Lox-induced ferroptosis is crucial.(75) 15-Lox selectively catalyzes PE-AA oxidation and executes ferroptotic cell death.”
• Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “Additionally, 12-lipoxygenase is required for p53-dependent ferroptosis (Chu et al., 2019).”
• The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “In this pathway, p53 indirectly activates the function of 12-LOX through transcriptional inhibition of SLC7A11, leading to 12-LOX-dependent ferroptosis upon ROS stress.(31) These findings delineate that both ACSL4/LPCAT3/15-LOX and p53/ SLC7A11/12-LOX pathways contribute to lethal LPO production dur”