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Inhibiting the syst...
Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation
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Liu, DS (author)
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Duong, CP (author)
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Haupt, S (author)
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Montgomery, KG (author)
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House, CM (author)
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Azar, WJ (author)
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Pearson, HB (author)
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Fisher, OM (author)
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Read, M (author)
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Guerra, GR (author)
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Haupt, Y (author)
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Cullinane, C (author)
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- Wiman, KG (author)
- Karolinska Institutet
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Abrahmsen, L (author)
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Phillips, WA (author)
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Clemons, NJ (author)
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(creator_code:org_t)
- 2017-03-28
- 2017
- English.
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8, s. 14844-
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Abstract
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- TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system xC−, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System xC− inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that SLC7A11 expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system xC− antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11–glutathione axis.
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- By the author/editor
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Liu, DS
-
Duong, CP
-
Haupt, S
-
Montgomery, KG
-
House, CM
-
Azar, WJ
-
show more...
-
Pearson, HB
-
Fisher, OM
-
Read, M
-
Guerra, GR
-
Haupt, Y
-
Cullinane, C
-
Wiman, KG
-
Abrahmsen, L
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Phillips, WA
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Clemons, NJ
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show less...
- Articles in the publication
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Nature communica ...
- By the university
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Karolinska Institutet