| Literature DB >> 25490448 |
Carole Sourbier1, Christopher J Ricketts1, Shingo Matsumoto2, Daniel R Crooks1, Pei-Jyun Liao1, Philip Z Mannes1, Youfeng Yang1, Ming-Hui Wei1, Gaurav Srivastava1, Sanchari Ghosh1, Viola Chen1, Cathy D Vocke1, Maria Merino3, Ramaprasad Srinivasan1, Murali C Krishna2, James B Mitchell2, Ann Marie Pendergast4, Tracey A Rouault5, Len Neckers1, W Marston Linehan6.
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.Entities:
Mesh：
Substances：
Year: 2014 PMID： 25490448 PMCID： PMC4386283 DOI： 10.1016/j.ccell.2014.10.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743