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Activation of Oxida...
Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino Acids
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LeBoeuf, S. E. (författare)
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Wu, W. R. L. (författare)
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Karakousi, T. R. (författare)
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Karadal, B. (författare)
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Jackson, S. R. (författare)
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Davidson, S. M. (författare)
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Wong, K. K. (författare)
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Koralov, S. B. (författare)
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- Sayin, Volkan I., 1983 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Wallenberg Centre for Molecular and Translational Medicine,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Surgery
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Papagiannakopoulos, T. (författare)
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(creator_code:org_t)
- Elsevier BV, 2020
- 2020
- Engelska.
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 31:2, s. 339-350
- Relaterad länk:
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http://www.cell.com/...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Rewiring of metabolic pathways is a hallmark of tumorigenesis as cancer cells acquire novel nutrient dependencies to support oncogenic growth. A major genetic subtype of lung adenocarcinoma with KEAP1/NRF2 mutations, which activates the endogenous oxidative stress response, undergoes significant metabolic rewiring to support enhanced antioxidant production. We demonstrate that cancers with high antioxidant capacity exhibit a general dependency on exogenous non-essential amino acids (NEAAs) that is driven by the Nrf2-dependent secretion of glutamate through system x(c)(-) (XCT), which limits intracellular glutamate pools that are required for NEAA synthesis. This dependency can be therapeutically targeted by dietary restriction or enzymatic depletion of individual NEAAs. Importantly, limiting endogenous glutamate levels by glutaminase inhibition can sensitize tumors without alterations in the Keap1/Nrf2 pathway to dietary restriction of NEAAs. Our findings identify a metabolic strategy to therapeutically target cancers with genetic or pharmacologic activation of the Nrf2 antioxidant response pathway by restricting exogenous sources of NEAAs.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- glutamine-metabolism
- lung-cancer
- serine
- biosynthesis
- glucose
- cells
- requirement
- sensitivity
- expression
- inhibitors
- Cell Biology
- Keap1
- NRF2
- amino acid synthesis
- asparaginase
- non-essential amino acids
- oxidative stress
- Endocrinology & Metabolism
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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