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. 2017 Jul 5;4(5):e1344757.
doi: 10.1080/23723556.2017.1344757. eCollection 2017.

Inhibiting system xC- and glutathione biosynthesis - a potential Achilles' heel in mutant-p53 cancers

Nicholas J Clemons  1   2 , David S Liu  1   2   3   4 , Cuong P Duong  3 , Wayne A Phillips  1   2   3   5
Affiliations

Inhibiting system xC- and glutathione biosynthesis - a potential Achilles' heel in mutant-p53 cancers

Nicholas J Clemons et al. Mol Cell Oncol. .

Abstract

Effective therapeutic strategies to target mutant tumor protein p53 (TP53, best known as p53) cancers remain an unmet medical need. We found that mutant p53 impairs the function of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, commonly known as NRF2), suppresses solute carrier family 7 member 11 (SLC7A11) expression, and diminishes cellular glutamate/cystine exchange. This decreases glutathione biosynthesis, resulting in redox imbalance VSports手机版. Mutant p53 tumors are thus inherently susceptible to further perturbations of the SLC7A11/glutathione axis. .

Keywords: APR-246; NFE2L2; NRF2; PRIMA-1met; SLC7A11; glutathione (GSH); p53; reactive oxygen species (ROS); system xC−; xCT V体育安卓版. .

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Figures

Figure 1.
Figure 1.
Accumulation of mutant tumor protein p53 (TP53) raises basal oxidative stress and induces susceptibility to glutathione depletion (a) Accumulation of mutant TP53 (shown as mutp53) in cancer cells impairs nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, best known as NRF2) function and reduces the expression of NRF2 target genes, including solute carrier family 7 member 11 (SLC7A11, also known as xCT), the cystine (Cys)/ glutamate (Glu) anti-porter. This results in reduced glutathione synthesis and higher basal oxidative stress compared with normal cells. In the absence of wild-type p53 tumor suppressor function, increased oxidative stress likely contributes to tumourigenesis via oxidative DNA damage and genomic instability. (b) As a consequence, cancer cells with accumulation of mutant p53 protein are sensitive to the glutathione depleting effects of methylene quinuclidinone (MQ, the active derivative of APR-246) or inhibition of SLC7A11. Binding of MQ also restores wild-type p53 transcriptional activity to mutant p53 and disrupts the interaction between mutant p53 and NRF2. This latter effect results in upregulation of SLC7A11 in response to oxidative stress, providing the mechanistic rationale for combining APR-246 with SLC7A11 inhibitors.
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