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Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.
Akiyama, Hiroki; Zhao, Ran; Ostermann, Lauren B; Li, Ziyi; Tcheng, Matthew; Yazdani, Samar J; Moayed, Arman; Pryor, Malcolm L; Slngh, Sandeep; Baran, Natalia; Ayoub, Edward; Nishida, Yuki; Mak, Po Yee; Ruvolo, Vivian R; Carter, Bing Z; Schimmer, Aaron D; Andreeff, Michael; Ishizawa, Jo.
Afiliación
  • Akiyama H; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Zhao R; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ostermann LB; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Li Z; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Tcheng M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Yazdani SJ; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Moayed A; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Pryor ML; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Slngh S; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Baran N; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ayoub E; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Nishida Y; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Mak PY; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ruvolo VR; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Carter BZ; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Schimmer AD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Andreeff M; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ishizawa J; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. JIshizawa@mdanderson.org.
Leukemia ; 38(4): 729-740, 2024 Apr.
Article en En | MEDLINE | ID: mdl-38148395
ABSTRACT
Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q10 (CoQ) recycling for its function of anti-lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition-mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition-mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Ferroptosis Límite: Humans Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Ferroptosis Límite: Humans Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido