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Mitochondrial Aconitase ACO2 Links Iron Homeostasis with Tumorigenicity in Non-Small Cell Lung Cancer.
Mirhadi, Shideh; Zhang, Wen; Pham, Nhu-An; Karimzadeh, Fereshteh; Pintilie, Melania; Tong, Jiefei; Taylor, Paul; Krieger, Jonathan; Pitcher, Bethany; Sykes, Jenna; Wybenga-Groot, Leanne; Fladd, Christopher; Xu, Jing; Wang, Tao; Cabanero, Michael; Li, Ming; Weiss, Jessica; Sakashita, Shingo; Zaslaver, Olga; Yu, Man; Caudy, Amy A; St-Pierre, Julie; Hawkins, Cynthia; Kislinger, Thomas; Liu, Geoffrey; Shepherd, Frances A; Tsao, Ming-Sound; Moran, Michael F.
Afiliação
  • Mirhadi S; Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Zhang W; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Pham NA; Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Karimzadeh F; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Pintilie M; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Tong J; Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Taylor P; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Krieger J; Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Pitcher B; Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Sykes J; SPARC BioCentre, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Wybenga-Groot L; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Fladd C; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Xu J; SPARC BioCentre, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Wang T; SPARC BioCentre, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Cabanero M; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Li M; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Weiss J; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Sakashita S; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Zaslaver O; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Yu M; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Caudy AA; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • St-Pierre J; Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Hawkins C; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Kislinger T; Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Québec, Canada.
  • Liu G; Department of Biochemistry, Microbiology, and Immunology and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.
  • Shepherd FA; Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Tsao MS; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Moran MF; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Mol Cancer Res ; 21(1): 36-50, 2023 01 03.
Article em En | MEDLINE | ID: mdl-36214668
ABSTRACT
The ability of a patient tumor to engraft an immunodeficient mouse is the strongest known independent indicator of poor prognosis in early-stage non-small cell lung cancer (NSCLC). Analysis of primary NSCLC proteomes revealed low-level expression of mitochondrial aconitase (ACO2) in the more aggressive, engrafting tumors. Knockdown of ACO2 protein expression transformed immortalized lung epithelial cells, whereas upregulation of ACO2 in transformed NSCLC cells inhibited cell proliferation in vitro and tumor growth in vivo. High level ACO2 increased iron response element binding protein 1 (IRP1) and the intracellular labile iron pool. Impaired cellular proliferation associated with high level ACO2 was reversed by treatment of cells with an iron chelator, whereas increased cell proliferation associated with low level ACO2 was suppressed by treatment of cells with iron. Expression of CDGSH iron-sulfur (FeS) domain-containing protein 1 [CISD1; also known as mitoNEET (mNT)] was modulated by ACO2 expression level and inhibition of mNT by RNA interference or by treatment of cells with pioglitazone also increased iron and cell death. Hence, ACO2 is identified as a regulator of iron homeostasis and mNT is implicated as a target in aggressive NSCLC. IMPLICATIONS FeS cluster-associated proteins including ACO2, mNT (encoded by CISD1), and IRP1 (encoded by ACO1) are part of an "ACO2-Iron Axis" that regulates iron homeostasis and is a determinant of a particularly aggressive subset of NSCLC.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Pulmonar de Células não Pequenas / Neoplasias Pulmonares Limite: Animals Idioma: En Revista: Mol Cancer Res Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Pulmonar de Células não Pequenas / Neoplasias Pulmonares Limite: Animals Idioma: En Revista: Mol Cancer Res Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Canadá