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

Abstract

Summary 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 ROS stress and abrogates p53-dependent inhibition of tumor growth in xenograft models, suggesting that ALOX12 is critical for p53-mediated ferroptosis. The ALOX12 gene resides on human chromosome 17p13.1, a hot spot 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 tumor suppression.

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…Loss of P53 prevents nuclear accumulation of dipeptidyl-peptidase-4 (DPP4) and thus facilitates plasma membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis (Xie et al, 2017), and p53 suppresses ferroptosis through the induction of cyclindependent kinase inhibitor 1A (CDKN1A/p21) expression by reduced accumulation of toxic lipid-ROS (Tarangelo et al, 2018;Kang et al, 2019). Arachidonate 12-lipoxygenase (ALOX12) inactivation diminishes p53-mediated ferroptosis induced by ROS stress (Chu et al, 2019). Interestingly, p53 also plays a negative role in ferroptosis regulation.…”

Ferroptosis: Final destination for cancer?

“…SlC7A11 could bind to ALOX12 and thus inhibit the lipoxygenase activity of ALOX12. p53 can upregulate the enzymatic activity of ALOX12 by repressing SLC7A11 expression . In these conditions, p53 acts as a positive regulator of ferroptosis.…”

Recent Progress in Ferroptosis Inducers for Cancer Therapy

“…Despite the important role of ferroptosis in sustaining survival of normal cells and tissues, it has been increasingly recognized that some oncogenic pathways are related to ferroptosis, rendering cancer cells extremely vulnerable to ferroptotic death . As one of the most well‐studied tumor suppressor genes, p53 inhibits the expression of cystine/glutamate antiporter transcriptionally, thus positively regulates ferroptosis pathway . In addition, mitochondrial tumor suppressor fumarase has been found necessary for cysteine‐deprivation‐induced ferroptosis .…”