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PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression.
Yang, Xin; Wang, Zhe; Samovich, Svetlana N; Kapralov, Alexander A; Amoscato, Andrew A; Tyurin, Vladimir A; Dar, Haider H; Li, Zhiming; Duan, Shoufu; Kon, Ning; Chen, Delin; Tycko, Benjamin; Zhang, Zhiguo; Jiang, Xuejun; Bayir, Hülya; Stockwell, Brent R; Kagan, Valerian E; Gu, Wei.
Afiliação
  • Yang X; Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
  • Wang Z; Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
  • Samovich SN; Center for Free Radical and Antioxidant Health and Departments of Environmental Health, Chemistry, Pharmacology and Chemical Biology, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pediatrics, Division of Critical Care and Hospital Medicine, Redox Health Cente
  • Kapralov AA; Center for Free Radical and Antioxidant Health and Departments of Environmental Health, Chemistry, Pharmacology and Chemical Biology, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • Amoscato AA; Center for Free Radical and Antioxidant Health and Departments of Environmental Health, Chemistry, Pharmacology and Chemical Biology, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • Tyurin VA; Center for Free Radical and Antioxidant Health and Departments of Environmental Health, Chemistry, Pharmacology and Chemical Biology, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • Dar HH; Center for Free Radical and Antioxidant Health and Departments of Environmental Health, Chemistry, Pharmacology and Chemical Biology, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • Li Z; Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
  • Duan S; Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
  • Kon N; Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
  • Chen D; Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
  • Tycko B; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA.
  • Zhang Z; Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Department of Pediatrics and Department of Genetics and Development, Vagelos College of Physicians & Surgeons, Columbia Univer
  • Jiang X; Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • Bayir H; Center for Free Radical and Antioxidant Health and Departments of Environmental Health, Chemistry, Pharmacology and Chemical Biology, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pediatrics, Division of Critical Care and Hospital Medicine, Redox Health Cente
  • Stockwell BR; Department of Chemistry, Columbia University, New York, NY 10027, USA; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Kagan VE; Center for Free Radical and Antioxidant Health and Departments of Environmental Health, Chemistry, Pharmacology and Chemical Biology, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • Gu W; Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY 10032, U
Cell Metab ; 36(4): 762-777.e9, 2024 Apr 02.
Article em En | MEDLINE | ID: mdl-38309267
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Limite: Animals Idioma: En Revista: Cell Metab Assunto da revista: METABOLISMO Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Limite: Animals Idioma: En Revista: Cell Metab Assunto da revista: METABOLISMO Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos