PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression Journal Article
| Authors: | Yang, X.; Wang, Z.; Samovich, S. N.; Kapralov, A. A.; Amoscato, A. A.; Tyurin, V. A.; Dar, H. H.; Li, Z.; Duan, S.; Kon, N.; Chen, D.; Tycko, B.; Zhang, Z.; Jiang, X.; Bayir, H.; Stockwell, B. R.; Kagan, V. E.; Gu, W. |
| Article Title: | PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression |
| Abstract: | Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killing neutrophils and thus unexpectedly stimulate tumor growth, raising a serious issue about whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through the peroxidation of phosphatidic acid (PA) upon high levels of reactive oxygen species (ROS). ROS-induced ferroptosis is critical for tumor growth in the absence of common ferroptosis inducers; strikingly, loss of PHLDA2 abrogates ROS-induced ferroptosis and promotes tumor growth but has no obvious effect in normal tissues in both immunodeficient and immunocompetent mouse tumor models. These data demonstrate that PHLDA2-mediated PA peroxidation triggers a distinct ferroptosis response critical for tumor suppression and reveal that PHLDA2-mediated ferroptosis occurs naturally in vivo without any treatment from ferroptosis inducers. © 2024 Elsevier Inc. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; unclassified drug; human cell; liver cell carcinoma; nonhuman; neoplasm; neoplasms; mouse; animal; metabolism; animals; mice; animal tissue; cell death; tumor volume; animal experiment; animal model; small interfering rna; tumor xenograft; physiology; b lymphocyte; disease model; cancer inhibition; b cell lymphoma; messenger rna; protein purification; liver tumor; western blotting; cell membrane; plasmid; reactive oxygen species; reactive oxygen metabolite; tumor immunity; genome; real time polymerase chain reaction; phosphatidylethanolamine; tumor growth; immune deficiency; disease models, animal; lipid peroxidation; oxidation; liposome; glutathione; acyltransferase; phosphatidic acid; tumor suppression; phospholipid; ros; liquid chromatography-mass spectrometry; diacylglycerol kinase; cystine; polyunsaturated fatty acid; high throughput sequencing; ferroptosis; metabolic stress; phospholipase d; pleckstrin; human; article; pleckstrin homology domain; cancer cell line; cell viability assay; diethylnitrosamine; polyphosphoinositide; arachidonate 12 lipoxygenase; crispr-cas9 system; alox12; cystine starvation; gpat3; phlda2; 1 acyl sn glycerol 3 phosphate o acylransferase; phospholipid binding protein; pleckstrin homology like domain family a member 2; diethylnitrosamine-induced hepatocarcinogenesis |
| Journal Title: | Cell Metabolism |
| Volume: | 36 |
| Issue: | 4 |
| ISSN: | 1550-4131 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2024-04-02 |
| Start Page: | 762 |
| End Page: | 777.e9 |
| Language: | English |
| DOI: | 10.1016/j.cmet.2024.01.006 |
| PUBMED: | 38309267 |
| PROVIDER: | scopus |
| PMCID: | PMC11209835 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
