Your browser doesn't support javascript.
loading
Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer.
Sourbier, Carole; Ricketts, Christopher J; Matsumoto, Shingo; Crooks, Daniel R; Liao, Pei-Jyun; Mannes, Philip Z; Yang, Youfeng; Wei, Ming-Hui; Srivastava, Gaurav; Ghosh, Sanchari; Chen, Viola; Vocke, Cathy D; Merino, Maria; Srinivasan, Ramaprasad; Krishna, Murali C; Mitchell, James B; Pendergast, Ann Marie; Rouault, Tracey A; Neckers, Len; Linehan, W Marston.
Affiliation
  • Sourbier C; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Ricketts CJ; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Matsumoto S; Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Crooks DR; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Liao PJ; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Mannes PZ; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Yang Y; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Wei MH; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Srivastava G; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Ghosh S; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Chen V; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Vocke CD; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Merino M; Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
  • Srinivasan R; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Krishna MC; Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Mitchell JB; Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Pendergast AM; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
  • Rouault TA; Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, MD 20892, USA.
  • Neckers L; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Linehan WM; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: wml@nih.gov.
Cancer Cell ; 26(6): 840-850, 2014 Dec 08.
Article in En | MEDLINE | ID: mdl-25490448
ABSTRACT
Patients with germline fumarate hydratase (FH) mutation are predisposed to develop aggressive kidney cancer with few treatment options and poor therapeutic outcomes. Activity of the proto-oncogene ABL1 is upregulated in FH-deficient kidney tumors and drives a metabolic and survival signaling network necessary to cope with impaired mitochondrial function and abnormal accumulation of intracellular fumarate. Excess fumarate indirectly stimulates ABL1 activity, while restoration of wild-type FH abrogates both ABL1 activation and the cytotoxicity caused by ABL1 inhibition or knockdown. ABL1 upregulates aerobic glycolysis via the mTOR/HIF1α pathway and neutralizes fumarate-induced proteotoxic stress by promoting nuclear localization of the antioxidant response transcription factor NRF2. Our findings identify ABL1 as a pharmacologically tractable therapeutic target in glycolytically dependent, oxidatively stressed tumors.
Subject(s)
Fulltext
Add to My VHL
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Quinazolines / Proto-Oncogene Proteins c-abl / Oxidative Stress / Fumarate Hydratase / Kidney Neoplasms Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2014 Document type: Article Affiliation country: United States
Fulltext
Add to My VHL
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Quinazolines / Proto-Oncogene Proteins c-abl / Oxidative Stress / Fumarate Hydratase / Kidney Neoplasms Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2014 Document type: Article Affiliation country: United States