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The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma.
Lin, Shengchen; Huang, Chongbiao; Sun, Jianwei; Bollt, Oana; Wang, Xiuchao; Martine, Eric; Kang, Jiaxin; Taylor, Matthew D; Fang, Bin; Singh, Pankaj K; Koomen, John; Hao, Jihui; Yang, Shengyu.
Afiliación
  • Lin S; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  • Huang C; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • Sun J; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  • Bollt O; State Key Laboratory of Natural Resource Conservation and Utilization in Yunnan and Center for Life Science, School of Life Sciences, Yunnan University, Kunming, China.
  • Wang X; South China Agricultural University, Guangzhou, China.
  • Martine E; Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  • Kang J; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  • Taylor MD; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • Fang B; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  • Singh PK; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  • Koomen J; South China Agricultural University, Guangzhou, China.
  • Hao J; Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  • Yang S; Department of Molecular Oncology, Proteomics & Metabolomics Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
EMBO Mol Med ; 11(12): e10849, 2019 12.
Article en En | MEDLINE | ID: mdl-31633874
The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate-limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self-renewal of lung cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK-mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline-inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC-mediated therapy resistance and metastatic recurrence.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Fosfotransferasas (Aceptor de Grupo Alcohol) / Neoplasias Pulmonares / Mitocondrias Límite: Humans Idioma: En Revista: EMBO Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Fosfotransferasas (Aceptor de Grupo Alcohol) / Neoplasias Pulmonares / Mitocondrias Límite: Humans Idioma: En Revista: EMBO Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido