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- Title
Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers.
- Authors
Arimichi Okazaki; Gameiro, Paulo A.; Christodoulou, Danos; Laviollette, Laura; Schneider, Meike; Chaves, Frances; Stemmer-Rachamimov, Anat; Yazinski, Stephanie A.; Lee, Richard; Stephanopoulos, Gregory; Lee Zou; Iliopoulos, Othon; Okazaki, Arimichi; Zou, Lee
- Abstract
Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis. Glutaminase 1 (GLS1) inhibitors depleted pyrimidines and increased ROS in VHL-/- cells but not in VHL+/+ cells, which utilized glucose oxidation for glutamate and aspartate production. GLS1 inhibitor-induced nucleoside depletion and ROS enhancement led to DNA replication stress and activation of an intra-S phase checkpoint, and suppressed the growth of VHL-/- RCC cells. These effects were rescued by administration of glutamate, αKG, or nucleobases with N-acetylcysteine. Further, we observed that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib synergizes with GLS1 inhibitors to suppress the growth of VHL-/- cells in vitro and in vivo. This work describes a mechanism that explains the sensitivity of RCC tumor growth to GLS1 inhibitors and supports the development of therapeutic strategies for targeting VHL-deficient RCC.
- Subjects
VON Hippel-Lindau disease; GLUTAMINASES; PYRIMIDINE synthesis; RENAL cancer diagnosis; KETOGLUTARATE dehydrogenase
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 5, p1631
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI87800